Pyridinecarboxyimidamide compounds and the use thereof

ABSTRACT

Disclosed are pyridinecarboximidamides having a vasodilating effect (hypotensive activity or antianginal activity), and acid adduct salts thereof. ##STR1## wherein when R 1  represents an alkyl, hydroxyalkyl, carboxyl, amino, acylamino, alkylamino, dialkylamino, aralkylamino, alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group, R 2  represents a hydrogen atom and R 3  represents a nitroxyl, 2-chlorophenyl or phenyl group; and 
     when R 1  represents a hydrogen atom, R 2  represents an alkyl, hydroxyalkyl, carboxyl, amino, acylamino, alkylamino, dialkylamino, aralkylamino, alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group and R 3  represents a nitroxyl, 2-chlorophenyl or phenyl group. 
     There is also disclosed the use of the compounds represented by the formula (I) for antihypertensive or antianginal purpose.

This application is a 371 of PCT/JP 93/00103, filed Jan. 28, 1993.

TECHNICAL FIELD

The present invention relates to novel pyridinecarboximidamide compoundshaving a vasodilating effect.

BACKGROUND ART

Prior to the accomplishment of the present invention, we found thatvarious N-cyano-carboximidamide compounds had a hypotensive activity, avasodilating effect and the like (as described in Japanese Laid-OpenPatent Publications Nos. 163061/1991 and 218343/1991). However, moreexcellent novel antihypertensive or antianginal agents are stronglydemanded when the various conditions of diseases, the quality of life,that is, the support and improvement of patients' daily life, sideeffects of drugs and the like are taken into consideration.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel compounds havinga vasodilating effect, and more specifically compounds having anantihypertensive effect or an antianginal effect. The present inventionhas been accomplished on the basis of the finding that novelpyridinecarboximidamide compounds have a vasodilating effect.

The pyridinecarboximidamide compounds according to the present inventionare represented by the following formula (I): ##STR2## wherein

when R¹ represents an alkyl, hydroxyalkyl, carboxyl, amino, acylamino,alkylamino, dialkylamino, aralkylamino, alkylsulfonamide,bisalkylsulfonylamino or hydroxyl R² represents a hydrogen atom and R³represents a nitroxyl, 2-chlorophenyl or phenyl group; and

when R¹ represents a hydrogen atom, represents R² represents ahydroxyalkyl, carboxyl, amino, acylamino, alkylamino, dialkylamino,aralkylamino, alkylsulfonamide, bisalkylsulfonylamino or hydroxyl groupand R³ represents a nitroxyl, 2-chlorophenyl or phenyl group.

The present invention also relates to use of the compounds mentionedabove. That is, the antihypertensive agent according to the presentinvention comprises as an active ingredient a pyridinecarboximidamiderepresented by formula (I) above or an acid adduct salt thereof, and theantianginal agent comprises as an active ingredient apyridinecarboximidamide represented by formula (I) above wherein R³ is anitroxyl group or an acid adduct salt thereof.

The present invention further relates to a method for treatment ofhypertension characterized in that a pyridinecarboximidamide representedby formula (I) or an acid adduct salt thereof is administered to apatient who needs the treatment of hypertension and to a method fortreatment of angina pectoris characterized in that apyridinecarboximidamide represented by formula (I) wherein R³ is anitroxy group or an acid adduct salt thereof is administered to apatient of angina pectoris.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a reaction scheme for producing the compound of the presentinvention represented by the formula (I) and illustrates the productionof the N-cyano-pyridinecarboximidamide compound represented by theformula (I) in which R¹ represents an alkyl group, a hydroxyalkyl group,a carboxyl group, an amino group, an alkylamino group, a dialkylaminogroup, an aralkylamino group or a hydroxyl group, and R² represents ahydrogen atom; or R¹ represents a hydrogen atom, and R² represents anamino group or a dialkylamino group, and an acid adduct salt thereof.

FIG. 2 is a reaction scheme for the production of the compound of thepresent invention represented by the formula (I) and illustrates theproduction of the N-ecyano-pyridinecarboximidamide compound in which R¹represents an acylamino group, an alkylsulfonamide group orbisalkylsulfonylamino group, and an acid adduct salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION PYRIDINECARBOXIMIDAMIDECOMPOUNDS

As described above, the pyridinecarboximidamide compounds according tothe present invention are represented by the following formula (I):##STR3## wherein

when R¹ represents an alkyl, hydroxyalkyl, carboxyl, amino, acylamino,alkylamino, dialkylamino, aralkylamino, alkylsulfonamide,bisalkylsulfonylamino or hydroxyl group, R² represents a hydrogen atomand R³ represents a nitroxyl, 2-chlorophenyl or phenyl group; and

when R¹ represents a hydrogen atom, R² represents a hydroxyalkyl,carboxyl, amino, acylamino, alkylamino, dialkylamino, aralkylamino,alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group and R³represents a nitroxyl, 2-chlorophenyl or phenyl group.

The compounds of the present invention in which R³ is a 2-chlorophenylor phenyl group in formula (I) are represented by formula (I-a) and thecompounds of the present invention in which R³ is a nitroxyl group informula (I) are represented by formula (I-b) (FIG. 1).

In R¹ and R² in formulae (I), (I-a) and (I-b), preferably, the alkylgroup has 1 to 5 carbon atoms, alkyl of the hydroxyalkyl group has 1 to5 carbon atoms, acyl of the acylamino group is acetyl, propionyl orbenzoyl, alkyl of the alkylamino group has 1 to 5 carbon atoms, alkyl ofthe dialkylamino group has 1 to 5 carbon atoms, the aralkylamino groupis benzylamino, alkyl of the alkylsulfonamide group has 1 to 5 carbonatoms, and alkyl of the bisalkylsulfonylamino group has 1 to 5 carbonatoms.

The compounds of the present invention possess a basic nitrogen atom, sothat they can form acid adduct salts. Acids which can be used for theformation of the acid adduct salts include, for instance, inorganicacids such as hydrochloric acid, sulfuric acid, nitric acid andphosphoric acid, and organic acids such as acetic acid, propionic acid,maleic acid, oleic acid, palmitic acid, citric acid, succinic acid,tartaric acid, fumaric acid, glutamic acid, pantothenic acid,methanesulfonic acid, toluenesulfonic acid and laurylsulfonic acid. Itis needless to say that pharmaceutically acceptable acids should be usedfor the formation of acid adduct salts which will be used as medicines.

As the representative examples of the pyridinecarboximidamide compoundsaccording to the present invention represented by the formula (I), thefollowing compounds are mentioned:

(1) In the case where R³ is a 2-chlorophenyl or phenyl group:

    ______________________________________                                        Compound No.                                                                             Name of Compound                                                   ______________________________________                                         1)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       methyl-3-pyridinecarboximidamide                                    2)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       ethyl-3-pyridinecarboximidamide                                     3)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       hydroxymethyl-3-pyridinecarboximidamide                             4)        5-carboxy-N-cyano-N'-[2-(2-                                                   chlorophenyl)ethyl]-3-                                                        pyridinecarboximidamide                                             5)        6-amino-N-cyano-N'-[2-(2-                                                     chlorophenyl)ethyl]-3-                                                        pyridinecarboximidamide                                                       (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(2-                                   aminopyridine)carboximidamide)                                      6)        5-amino-N-cyano-N'-[2-(2-                                                     chlorophenyl)ethyl]-3-                                                        pyridinecarboximidamide                                                       (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3-                                   aminopyridine)carboximidamide)                                      7)        5-acetamide-N-cyano-N'-[2-(2-chlorophenyl)-                                   ethyl]-3-pyridinecarboximidamide                                              (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-[3-                                   (N-acetylamino)pyridine]carboximidamide)                            8)        5-benzamide-N-cyano-N'-[2-(2-chlorophenyl)-                                   ethyl]-3-pyridinecarboximidamide                                    9)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       dimethylamino-3-pyridinecarboximidamide                            10)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       ethylamino-3-pyridinecarboximidamide                               11)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       isopropylamino-3-pyridinecarboximidamide                           12)        5-n-butylamino-N-cyano-N'-[2-(2-                                              chlorophenyl)ethyl]-3-                                                        pyridinecarboximidamide                                            13)        5-benzylamino-N-cyano-N'-[2-(2-                                               chlorophenyl)ethyl]-3-                                                        pyridinecarboximidamide                                            14)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       methanesulfonamide-3-                                                         pyridinecarboximidamide                                                       (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-[3-                                   (N-methanesulfonylamino)pyridine]-                                            carboximidamide)                                                   15)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-bis-                                   methanesulfonylamino-3-                                                       pyridinecarboximidamide                                                       (N-cyano-N' -[2-(2-chlorophenyl)ethyl]-5-[3-                                  (N,N-bismethanesulfonylamino)pyridine]-                                       carboximidamide)                                                   16)        5-amino-N-cyano-N'-(2-phenethyl)-3-pyridine-                                  carboximidamide                                                    17)        N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-                                       hydroxy-3-pyridinecarboximidamide                                  ______________________________________                                    

(2) In the case where R³ is a nitroxy group:

    ______________________________________                                        Compound No.                                                                             Name of Compound                                                   ______________________________________                                        18)        5-amino-N-cyano-N'-(2-nitroxyethyl)-3-                                        pyridinecarboximidamide                                                       (N-cyano-N'-(2-nitroxyethyl)-5-(3-amino-                                      pyridine)carboximidamide)                                          19)        N-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-                                   pyridinecarboximidamide                                                       (N-cyano-N'-(2-nitroxyethyl)-5-[3-(N-                                         ethylaminopyridine]carboximidamide)                                20)        6-amino-N-cyano-N'-(2-nitroxyethyl)-3-                                        pyridinecarboximidamide                                                       (N-cyano-N'-(2-nitroxyethyl)-5-(2-amino-                                      pyridine)carboximidamide)                                          21)        N-cyano-6-diethylamino-N'-(2-nitroxyethyl)-                                   3-pyridinecarboximidamide                                                     (N-cyano-N'-(2-nitroxyethyl)-5-[2-(N,N-                                       diethylamino)pyridine]carboximidamide)                             22)        5-n-butylamino-N-cyano-N'-(2-nitroxyethyl)-                                   3-pyridinecarboximidamide                                                     (N-cyano-N'-(2-nitroxyethyl)-5-[3-(N-n-                                       butylamino)pyridine]carboximidamide)                               23)        N-cyano-N'-(2-nitroxyethyl)-5-                                                isopropylamino-3-pyridinecarboximidamide                                      (N-cyano-N'-(2-nitroxyethyl)-5-[3-(N-                                         isopropylamino)pyridine]carboximidamide)                           24)        5-acetylamino-N-cyano-N'-(2-nitroxyethyl)-3-                                  pyridinecarboximidamide                                                       (N-cyano-N'-(2-nitroxyethyl)-5-[3-(N-acetyl-                                  amino)pyridine]carboximidamide)                                    ______________________________________                                    

Process for Preparing Pyridinecarboximidamide Compounds

The pyridinecarboximidamide compounds according to the present inventioncan be prepared by any method suitable for the purpose, and, forinstance, the following methods may be taken for the preparation of thecompounds.

A) Preparation of N-cyano-pyridinecarboximidamide compounds representedby the formula (I) wherein R¹ is an alkyl, hydroxyalkyl, carboxyl,amino, alkylamino, dialkylamino, aralkylamino or hydroxyl group and R²is a hydrogen atom, or R¹ is a hydrogen atom and R² is an amino ordialkylamino group, and acid adduct salts thereof:

Among the compounds of the present invention represented by the formula(I), those pyridinecarboximidamide compounds in which R¹ is an alkyl,hydroxyalkyl, carboxyl, amino, alkylamino, dialkylamino, aralkylamino orhydroxyl group and R² is a hydrogen atom, or in which R¹ is a hydrogenatom and R² is an amino or dialkylamino group can be prepared, as shownin FIG. 1, by leading cyanopyridine (II) having the above-described R¹and R² of the formula (I) to N-cyano-pyridinecarboximidate (IV) viapyridinecarboximidate (III), and then reacting theN-cyanopyridinecarboximidate (IV) with an amine (V) or (VI). It is notedthat a pyridinecarboximidamide compound whose R¹ is a carboxyl group canbe obtained by using cyanopyridine (II) whose R¹ is a methoxycarbonylgroup as the starting compound, leading it to a pyridinecarboximidamidecompound via pyridinecarboximidate (III) andN-cyano-pyridinecarboximidate (IV), and eliminating the methyl grouptherefrom. The explanation will be given below in order.

1) Cyanopyridine (II)

As mentioned above, among the compounds of the present inventionrepresented by the formula (I), those pyridinecarboximidamide compoundsin which R¹ is an alkyl, hydroxyalkyl, carboxyl, amino, alkylamino,dialkylamino, aralkylamino or hydroxyl group and R² is a hydrogen atom,or in which R¹ is a hydrogen atom and R² is an amino or dialkylaminogroup can be synthesized, as shown in FIG. 1, from cyanopyridine (II)having the above-mentioned R¹ and R². The cyanopyridine may be either aknown compound or a compound prepared by a known method as shown in, forinstance, Journal of Medicinal Chemistry 10, 149-154 (1967), Journal ofHeterocyclic Chemistry 11, 397-399 (1974), Heterocycles 22, 117-124(1984) or the like.

2)- Preparation of Pyridinecarboximidate (III)

As one of the methods for preparing pyridinecarboximidate (III) from thecyanopyridine (II), the Pinner's method can be mentioned. Namely, bytreating the cyanopyridine (II) with hydrogen chloride gas in analcohol, alkyl pyridinecarboximidate corresponding to the alcoholemployed can be obtained. Alcohols which can be used in the abovereaction include, for example, methanol, ethanol, 1-propanol,2-propanol, 1-butanol, isobutyl alcohol and t-butyl alcohol. The alcoholcan be used also as a reaction solvent. Furthermore, it can be usedsimply as a reagent in the coexistence of other solvents. When thealcohol is used also as a reaction solvent, the amount of the alcohol isusually in the range of 50 to 200 moles per 1 mole of the cyanopyridine.When the alcohol is used in the presence of other solvents, thepreferable amount of the alcohol is 1 to 5 moles per 1 mole of thecyanopyridine. Solvents which can be used in this reaction include, forexample, aprotic solvents such as hexane, benzene, toluene, diethylether and petroleum ether. The reaction temperature is preferably in therange of -10° to 50° C., particularly from 0° C. to room temperature.

The reaction can be completed, in general, in 1 to 24 hours under theabove-described reaction conditions.

The pyridinecarboximidate (III) obtained by above reaction is in theform of a hydrochloric acid salt. This salt can be supplied to thesucceeding reaction either as it is or after the neutralization ofhydrochloric acid with an alkali. Moreover, it is possible to subjectthe pyridinecarboximidate (III) or its hydrochloric acid salt toisolation and purification. In this case, any one of the purificationmethods conventionally known in the field of organic chemistry, such ascrystallization, distillation and column chromatography using silica gelas a support, can be taken.

The pyridinecarboximidate (III) can also be prepared by another method.Namely, the pyridinecarboximidate (III) can be obtained by treating thecyanopyridine (II) with a catalytic amount of a metal alcoholate in analcohol. Sodium alcoholate and potassium alcoholate can be mentioned asexamples of the metal alcoholate. Alcohols which can be used in thisreaction and the amount thereof are the same as those described in thepreparation process according to the Pinner's method. Further, thisreaction can be carried out also in the coexistence of other solvents asdescribed above, and solvents which can be used in this reaction are thesame as those mentioned above. The reaction temperature is preferably inthe range of the freezing point of the solvent used to 30° C.,particularly from 0° to 10° C. The reaction can be completed, ingeneral, in 12 to 24 hours.

The isolation and purification of the pyridinecarboximidate obtained bythis reaction can be conducted by the same method as is shown in theabove.

3) Conversion into N-cyano-pyridinecarboximidate (IV)

The above-obtained pyridinecarboximidate (III) or its hydrochloric acidsalt is converted into N-cyano-pyridinecarboximidate (IV) when it isreacted with cyanamide.

The amount of the cyanamide used is preferably 1 mole or more,particularly 2 to 3 moles per 1 mole of the pyridinecarboximidate (III).This reaction depends on the pH of the reaction solution, and theoptimum pH range is preferably from 6.0 to 8.0, more preferably from 6.5to 7.5. In order to keep the pH in the above optimum range, it issuitable that the reaction is carried out in a phosphoric acid buffersolution, or with the addition of a base such as sodium carbonate when ahydrochloric acid salt is used as a substrate. Moreover, this reactioncan be carried out also in the coexistence of other solvents. Solventswhich can be used in the reaction include acetonitrile, dioxane,tetrahydrofuran and DMF. The reaction temperature is preferably in therange of 0° to 50° C., and around room temperature is particularlypreferred.

The reaction can be completed in 5 to 30 hours under the aforementionedreaction conditions.

The N-cyano-pyridinecarboximidate (IV) thus obtained can be isolated andpurified by the same method as is described above, such ascrystallization, distillation or column chromatography using silica gelas a support.

4) Preparation of N-cyano-pyridinecarboximidamide

N-Cyano-pyridinecarboximidamides represented by the formulas (I-a) and(I-b) can be obtained by reacting the above-obtainedN-cyano-pyridinecarboximidate (IV) with an amine (V) and (VI),respectively. The suitable amount of the amine used is 1 mole or more,preferably from 1 to 2 moles per 1 mole of theN-cyano-pyridinecarboximidate (IV). This reaction is usually carried outin a solvent. Solvents which can be used in the reaction include, forexample, organic solvents such as methanol, ethanol, dichloromethane,chloroform, carbon tetrachloride, dioxane and tetrahydrofuran, andwater. The reaction temperature is in the range of 0° C. to the boilingpoint of the solvent used, and around room temperature is particularlypreferred. This reaction can be completed, in general, in 2 to 24 hoursunder the above-described reaction conditions.

The isolation and purification of the N-cyano-pyridinecarboximidamidesrepresented by the formula (I) ((I-a) and (I-b)) from the reactionsolution obtained by the above reaction can be conducted by the samemethod as is mentioned in the item of the isolation and purification ofthe pyridinecarboximidate (III).

The N-cyano-pyridinecarboximidamides ((I-a) and (Ib)) thus obtained canbe made into acid adduct salts by reacting them with an acid. Acidswhich can be used are the same as above.

B) Preparation of N-cyano-pyridinecarboximidamide compounds representedby the formula (I) wherein R¹ is an acylamino, alkylsulfonamide orbisalkylsulfonylamino group, and acid adduct salts thereof:

Among the compounds of the present invention represented by the formula(I), N-cyano-pyridinecarboximidamide in which R¹ is an acylamino,alkylsulfonamide or bisalkylsulfonylamino group can be prepared, asshown in FIG. 2, by using as the starting compound theN-cyano-pyridinecarboximidamide (I-c) having an amino group as R¹ in theformula (I) obtained by the above-described reaction, and subjecting theamino group which is bonded to pyridine to acylation, alkylsulfonylationor bisalkylsulfonylation. This preparation method will be morespecifically explained below.

The captioned compound represented by the formula (I-d) can be preparedby subjecting the amino group in the compound (I-c) to N-acylation orN-alkylsulfonylation. The N-acylation or N-alkylsulfonylation can becarried out by any one of various conventional manners, and, forinstance, the following manner may be taken for the purpose.

The compound (I-d) can be obtained by reacting the amino group in thecompound (I-c) with an acylating or sulfonylating agent such as an acidhalide, an acid anhydride or an active ester; or by reacting the aminogroup with carboxylic acid with the addition of a condensing agent suchas 1,3-dichlorohexylcarbodiimide (DCC) or1-ethyl-3-(3'-diethylaminopropyl)-carbodiimide (WSCI). In the case wherean acylating agent is used, the suitable amount of the acylating agentis 1 mole or more, preferably from 1 to 2 moles per 1 mole of thestarting compound (I-c). This reaction is usually carried out in asolvent. Solvents which can be used in the reaction include, forinstance, organic solvents such as pyridine, N,N-dimethylformamide,dichloromethane, chloroform, acetonitrile and tetrahydrofuran. It isdesirable to conduct the reaction in the presence of an organic basesuch as pyridine or triethylamine, or an inorganic base such aspotassium carbonate or sodium hydrogencarbonate. The reactiontemperature is in the range of 0° C. to the boiling point of the solventused, and around room temperature is particularly preferred. In the casewhere a condensing agent is used, it is suitable to conduct the reactionby using carboxylic acid and the condensing agent each in an amount of 1mole or more per 1 mole of the starting compound (I-c), preferably eachin an amount equimolar to the amount of the starting compound. When anadditive such as N-hydroxysuccinimide or N-hydroxybenzotriazole is usedin this reaction, the reaction proceeds promptly and the yield alsoincreases. This reaction is usually carried out in a solvent. Solventswhich can be used in the reaction include, for instance, organicsolvents such as N,N-dimethylformamide, acetonitrile andtetrahydrofuran. It is possible to conduct the reaction in water whenWSCI is used. The reaction temperature is in the range of 0° C. to theboiling point of the solvent used, and around room temperature isparticularly preferred.

These reactions can be completed, in general, in 2 to 24 hours under theabove-described two reaction conditions.

The isolation and purification of the pyridine-carboximidamiderepresented by the formula (I-d) from the reaction solution obtained bythe above reaction can be conducted by the same method as is describedin the item of the isolation and purification of thepyridinecarboximidate represented by the formula (III).

The N-cyano-pyridinecarboximidamide (I-d) thus prepared can be made intoan acid adduct salt by reacting it with an acid. Acids which can be usedin the reaction are the same as those described in the above.

Use of Pyridinecarboximidamide Compounds

(1) In the case where R³ in the formula (I) is a 2-chlorophenyl orphenyl group:

The pyridinecarboximidamide compounds according to the present inventionhave, as described before, a hypotensive activity. They are thereforeuseful as antihypertensive agents.

The pyridinecarboximidamide compounds of the present invention can beadministered, as antihypertensive agents, orally, parenterally(intramuscularly, subcutaneously, intravenously, percutaneously), or inthe form of a sublingual tablet or a suppository.

It is needless to say that the dose and the administration manner of thepyridinecarboximidamide compound of the present invention vary dependingon the state of a patient such as sex and sensitivity, the time foradministration, drugs to be used in combination, and the condition of apatient or a disease. In addition, the optimum dose and the frequency ofthe administration under a certain condition should be determined by aspecialist on the basis of the above-described guideline and the resultsof an optimum dose determining test. In general the dose per adultindividual is from about 0.1 to 200 mg, preferably from about 0.3 to 100mg, more preferably from 0.5 to 50 mg.

In the case of oral administration, the compound of the presentinvention is administered in the form of tablets, granules, powders or.capsules. In the case of parenteral administration, it is administeredin the form of injections or suspensions. Upon producing thesepharmaceutical preparations, excipients, binding agents, disintegratingagents, lubricants, stabilizers and the like may be added.

Examples of the excipients include lactose, starch, crystallinecellulose, mannitol, maltose, calcium hydrogen phosphate, lightanhydrous silicic acid and calcium carbonate. Examples of the bindingagents include starch, polyvinyl-pyrrolidone, hydroxypropylcellulose,ethylcellulose, carboxymethylcellulose and gum arabic. Examples of thedisintegrating agents include starch and carboxymethylcellulose.Examples of the lubricants include magnesium stearate, talc and hardenedoil. Examples of the stabilizing agents include lactose, mannitol,maltose, Polysorbates and polyoxyethylene hardened castor oil.

Pharmaceutical preparations in the forms of tablets, granules, capsules,injections and the like can be produced by using the above ingredients.

(2) In the case where R³ in the formula (I) is a nitroxyl group:

As mentioned previously, the pyridinecarboximidamide compounds accordingto the present invention have a vasodilating effect, more specifically ahypotensive activity or an antianginal effect. For this reason, they areuseful as antihypertensive or antianginal agents.

The pyridinecarboximidamide compounds according to the present inventioncan be administered, as antihypertensive or as antianginal agents,orally, parenterally (intramuscularly, subcutaneously, intravenously,percutaneously), or in the form of a sublingual tablet or a suppository.

It is needless to say that the dose and the administration manner of thepyridinecarboximidamide compound of the present invention vary dependingon the state of a patient such as sex and sensitivity, the time foradministration, drugs to be used in combination, and the condition of apatient or a disease. In addition, the optimum dose and the frequency ofthe administration under a certain condition should be determined by aspecialist on the basis of the above-described guideline and the resultsof an optimum dose determining test. In general, however, the dose peradult individual is from about 0.1 to 200 mg, preferably from about 0.5to 100 mg, more preferably from 0.5 to 50 mg.

In the case of oral administration, the compound of the presentinvention is administered in the form of tablets, granules, powders orcapsules. In the case of parenteral administration, it is administeredin the form of injections or suspensions. Upon producing thesepharmaceutical preparations, excipients, binding agents, disintegratingagents, lubricants, stabilizers and the like can be added.

Examples of the excipients include lactose, starch, crystallinecellulose, mannitol, maltose, calcium hydrogen phosphate, lightanhydrous silicic acid and calcium carbonate. Examples of the bindingagents include starch, polyvinyl-pyrrolidone, hydroxypropylcellulose,ethylcellulose, carboxymethylcellulose and gum arabic. Examples of thedisintegrating agents include starch and carboxymethyl-cellulose.Examples of the lubricants include magnesium stearate, talc and hardenedoil. Examples of the stabilizing agents include lactose, mannitol,maltose, Polysorbates and polyoxyethylene hardened castor oil.

Pharmaceutical preparations in the forms of tablets, granules, capsules,injections and the like can be produced by using the above ingredients.

As described above, pyridinecarboximidamide compounds according t o thepresent invention are novel compounds having a potent vasodilatingeffect, more specifically an antihypertensive effect or an antianginaleffect. As demonstrated in the Experimental Examples described below,the antihypertensive activity of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamidewas particularly determined with the passage of time, and, as a result,it was found that the activity was extremely potent and sustainable. Theantihypertensive activity or coronary vasodilating effect of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide was alsodetermined with the passage of time, and it was found to be remarkablypotent and sustainable. It can be said that such advantageous propertiesof the compounds are unexpected ones for the inventors of the presentinvention.

EXPERIMENTAL EXAMPLES

The present invention is further described in detail with reference topharmacological tests and examples below, but it should not be construedthat the invention is limited thereto.

(1) When R³ in the formula (I) represents a 2-chlorophenyl group or aphenyl group: Pharmacological Test 1: Antihypertensive activities onspontaneously hypertensive rat (intravenously)

Antihypertensive activities of the compounds of the present inventionwere observed with male spontaneously hypertensive rats (SHR).

Animals were anesthetized with urethane: α-chloralose.

A cannula was inserted into the carotid artery for measuring the meanblood pressure via a pressure transducer. A test compound wascumulatively administered through the cannula inserted into the femoralvein with an interval of 30 minutes. Variation of blood pressure wasdetermined as the percentage change in the blood pressure beforeadministration of the test compound, and the ED₂₀ (the dose whichlowered the blood pressure by 20%) was calculated from a dose-responsecurve.

Results

The ED₂₀ values of the representative compounds among the compounds ofthe present invention are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Compound No.   ED.sub.20 (μg/kg, i.v.)                                     ______________________________________                                        1              17.1                                                           2              7.0                                                            3              8.7                                                            5              33.3                                                           6              4.6                                                            7              12.3                                                           10             7.9                                                            16             28.0                                                           ______________________________________                                    

Pharmacological Test 2: Antihypertensive activity of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3-aminopyridine)carboximidamide;Compound No. 6) on beagles

Antihypertensive activities of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3aminopyridine)carboximidamide;Compound No. 6) according to the present invention was assessed bycomparison with those ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide which isthought to be a wellknown compound most similar to the compound of thepresent invention (see Japanese Patent Laid-Open Publication No.163061/1991).

Experiments were carried out with beagles (body weight, 9.2-10.4 kg)under anesthetization by intravenous administering 30 mg/kg ofpentobarbital sodium. A cannula was inserted into the right femoralartery for measuring blood pressure. The test compound was administeredthrough the cannula inserted into the right femoral artery.

Results

Dose-dependent decrease in blood pressure was observed by intravenouslyadministering 3-30 μg/kg of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.The duration of the antihypertensive action lasted 10, 45 and 60 min. atthe dose of 3, 10, and 30 μg/kg, respectively. While the decrease inblood pressure was observed on the administration of 10 and 30 μg/kg ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide, thedecrease in blood pressure induced by both doses were recovered within10 minutes after administration (as shown in Table 2).

                  TABLE 2                                                         ______________________________________                                        Antihypertensive effects of 5-amino-N-cyano-N'-                               [2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide                           administered intravenously                                                    Antihypertensive activity (%)                                                         5-Amino-N-cyano-N'-[2-(2-                                                                      N-Cyano-N'-[2-(2-                                            chlorophenyl)ethyl]-3-                                                                         chlorophenyl)ethyl]-3-                               Time after                                                                            pyridinecarboxyimidamide                                                                       pyridinecarboximidamide                              dosage  Dose (μg/kg)  Dose (μg/kg)                                      (min)   3       10       30    3    10    30                                  ______________________________________                                        0       0.0     0.0      0.0   0.0  0.0   0.0                                 1       -3.9    -16.0    -29.3 0.0  -23.4 -41.7                               2       -12.8   -22.7    -40.0 1.9  -17.7 -39.8                               3       -10.3   -26.7    -42.7 1.9  -13.1 -33.3                               5       -6.4    -26.7    -46.7      -4.7  -16.7                               7.5     -3.9    -26.7    -44.0            -2.8                                10      -3.9    -26.7    -42.7            -0.9                                15              -20.0    -40.0                                                20              -16.0    -36.0                                                30              -13.3    -33.3                                                45              -6.7     -24.0                                                60                       -16.0                                                ______________________________________                                    

Pharmacological Test 3: Antihypertensive activities of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3-aminopyridine)carboximidamide)on renal hypertensive beagles

Beagles (body weight, 9.0-11.0 kg) were anesthetized with 30 mg/kg ofpentobarbital sodium intravenously. The left renal artery was carefullyexposed through a flank incision, and wound with two silk sutures andligated together with a 18G needle (external diameter; 1.2 mm) at twopositions with the distance of 5 mm. A polyethylene tube for themeasurement of blood pressure (IMG, PE-100) was inserted into thefemoral artery, and the other terminal of the tube was exteriorized atthe back of the neck. The polyethylene tube was filled withphysiological saline containing 500 U/ml of heparin and sealed with asteel wire plug except on the measurement of the blood pressure.Antibiotics (penicilline and streptomycin, manufactured by Meiji Seika)were administered intramuscularly for three days after operation toprevent infections.

Beagles exhibiting an average blood pressure exceeding 120 mmHg after amonth of the operation were subjected to the experiment as2-kidney-1-clipped renal hypertensive dogs.

After5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamidewas put into a No. 3 gelatin capsule, a gap was filled with lactose (100mesh). The capsule was administered orally, and blood pressure wasmeasured for 24 hours after administering the drug. Measurement wascarried out without anesthetization under suspension with sling sheet.Blood pressure was measured by connecting the tube for measuring bloodpressure to a pressure transducer (TP-400T; manufactured by NihonKohden) and recorded on a polygraph.

Results

The successive decrease in blood pressure was observed on the oraladministration of 0.25 and 0.5 mg/kg of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamideaccording to the present invention (see Table 3). Table 3: Effect of5-amino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3-aminopyridine)carboximidamide)on the blood pressure of renal hypertensive beagles

    ______________________________________                                        Time after     Average blood pressure (mmHg)                                  administration Dose (mg/kg, p.o.)                                             (hour)         0.25      0.50                                                 ______________________________________                                        0              122.4 ± 4.4                                                                          126.6 ± 0.5                                       1              100.9 ± 7.4                                                                           68.1 ± 7.4                                       2               85.7 ± 0.3                                                                           84.8 ± 6.1                                       4              102.8 ± 3.9                                                                           99.7 ± 12.3                                      6              110.1 ± 2.6                                                                          106.2 ± 9.5                                       8              112.6 ± 3.4                                                                          114.4 ± 7.3                                       24             118.8 ± 4.8                                                                          111.8 ± 3.9                                       ______________________________________                                    

Pharmacological Test 4: Time Course of antihypertensive activity in SHR

Time course of antihypertensive activity of5-amino-N-cyano-N'-(2-phenethyl)pyridinecarboximidamide (Compound No.16) was examined.

(1) Test Method

Antihypertensive activity of the compound was observed in conscious malespontaneously hypertensive rats (SHR). Systolic blood pressure (SBP) wasmeasured with the tail cuff method.

The compound No. 16 was dissolved in an equivalent mixture ofpolyethylene glycol 200 and physiological saline, and administeredorally with the aid of an oral probe. SBP was measured beforeadministration and 1, 2, 4, 6, 8, 12 and 24 hours after administrationof the compound. The results were expressed as the percentage change inSBP obtained before administration.

(2) Results

The decrease in blood pressure was observed after the administration of3.0 mg/kg of the compound (16) and the antihypertensive effect lastedfor 12 hours or more (see Table 4). Table 4: Antihypertensive activityof 5-amino-N-cyano-N'-(2-phenethyl)pyridinecarboximidamide (Compound No.16) in SHR (Data are expressed as the percentage change in SBP obtainedbefore administration)

    ______________________________________                                        Com-                                                                          pound Time after administration (hour)                                        No.   1       2       4     6     8     12    24                              ______________________________________                                        16    -45.3   -23.9   -42.3 -27.9 -22.8 -15.1 -8.2                            ______________________________________                                    

Pharmacological Test 5: Acute toxicity

Acute toxicity of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(Compound No. 6) of the present invention on oral administration wasexamined with male SD rats (5 weeks old). As a result, no rats died atthe dose of 50 mg/kg. LD₅₀ was in the range over 50 mg/kg.

Example 1 Preparation of 3-cyano-5-methylpyridine

3-Cyano-5-methylpyridine is a well-known compound, which may beprepared, for example, by the methods described in Published EuropeanPatent No. 253360/1988; European Journal of Biochemistry, 118, 3,479-486 (1981); or Chemical and Pharmaceutical Bulletin, 22, 10,2402-2406 (1974). Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-methyl-3-pyridinecarboximidamide

3-Cyano-5-methylpyridine (2 g, 16.9 mmol) was dissolved in 1-propanol(100 ml). Sodium methoxide (46 mg, 0.85 mmol) was added, and theresulting mixture was stirred at 0° C. for 20 hours. After thecompletion of the reaction, the reaction mixture was neutralized withacetic acid (56 mg, 0.93 mmol), and the resulting mixture wasconcentrated under reduced pressure. After concentration, ethyl ether(50 ml) was added to the residue, and insoluble sodium acetate wasremoved by filtration. The filtrate was concentrated under reducedpressure to give a crude product of propyl5-methyl-3-pyridinecarboximidate.

To propyl 5-methyl-3-pyridinecarboximidate was then added an aqueoussolution (100 ml) of cyanamide (1.42 g, 33.8 mmol), Na₂ HPO₄ (2.40 g,16.9 mmol) and NaH₂ PO₄ ·2H₂ O (10.56 g, 67.7 mmol). The mixture wasstirred at room temperature for 5 hours and extracted with chloroform(100 ml×3). The chloroform layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure to give a crude product ofpropyl N-cyano-5-methyl-3-pyridinecarboximidate (2.54 g). IR (neat) cm⁻¹: 2200, 1610, 1320, 730.

Propyl N-cyano-5-methyl-3-pyridinecarboximidate (0.77 g, 3.8 mmol) thusobtained was next dissolved in methanol (5 ml), and 2-(2-chlorophenyl)ethylamine (0.59 g, 3.8 mmol) was added to the mixture. The resultingmixture was stirred at room temperature for 30 minutes. After thereaction mixture was concentrated under reduced pressure, it wassubjected to silica gel column chromatography (Wako Gel C-200, 30 g;eluted with chloroform:methanol=100:1) and crystallized frommethanol/diethyl ether to give the title compound (0.62 g, 2.1 mmol) ascolorless crystals (yield, 55%). IR (KBr) cm⁻ :2160, 1580, 1540, 1440,1210, 740,720. ¹ H-NMR (100 MHz, CDCl₃): δ (ppm)

8.98(1H, d, J=2.7Hz, H-6), 8.67(1H, d, J=1.8Hz, H-2), 8.27(1H, m, H-4),7.4-7.2(4H, C₆ H₄ Cl), 3.82(2H, dd, J=6.7, 12.8Hz, NHCH₂ CH₂ C₆ H₄ Cl),3.12(2H, t, J=6.7Hz, NHCH₂ CH₂ C₆ H₄ Cl), 2.47(3H, s, Pyridine-CH₃).

Example 2 Preparation of 3-cyano-5-ethylpyridine

5-Bromo-3-cyanopyridine (6.5 g) was dissolved in triethylamine (15 ml),and bis(triphenylphosphine)-palladium chloride [(Ph₃ P)₂ PdCl₂ ] (600mg), cuprous iodide (CuI) (350 mg) and trimethylsilylacetylene (TMSCCH)(7.5 ml) were added. The mixture was stirred in a tight sealed reactorat 100° C. for 60 minutes. After cooling, water (50 ml) was added to themixture and extracted with diethyl ether (50 ml×3). The diethyl etherlayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure to give a residue (6.87 g). The residue (4 g) was nextdissolved in tetrahydrofuran (30 ml), and a iN tetrahydrofuran solution(20 ml) of tetrabutylammonium fluoride (Bu₄ NF) was added to thesolution at 5° C. The mixture was stirred for 10 minutes while allowedto raise the temperature up to room temperature. An aqueous solution of1N sodium hydroxide (50 ml) was added to the reaction mixture andextracted with diethyl ether (50 ml×3). The diethyl ether layer wasdried over anhydrous sodium sulfate, concentrated at reduced pressureand subjected to silica gel column chromatography (Wako Gel C-200, 40 g;eluted with diethyl ether:hexane=1:1) to give 3-cyano-5-ethynylpyridine(1.84 g) as pale yellow solids (yield, 70%).

3-Cyano-5-ethynylpyridine (1 g) was dissolved in tetrahydrofuran (30 ml)and subjected to catalytic hydrogenation under hydrogen stream in thepresence of 10% palladium-carbon (100 mg) as a catalyst. After thecatalyst was removed by filtration, the filtrate was concentrated underreduced pressure to give 0.87 g of 3-cyano-5-ethylpyridine (yield, 84%).¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.58(1H, H-2), 8.39(1H, H-6), 7.77(1H,H-4), 2.72(2H, q, J=7.5Hz, Pyridine-CH₂ CH₃), 1.26(3H, t, J=7.5Hz,Pyridine-CH₂ CH₃).

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl-5-ethyl-3-pyridinecarboximidamide

After 3-cyano-5-ethylpyridine (2.07 g, 15.7 mmol) was dissolved in1-propanol (80 ml) and hydrogen chloride gas was passed into thesolution for 30 minutes, the reactor was tight sealed and the mixturewas stirred at room temperature for 30 hours. After the completion ofthe reaction, the reaction mixture was concentrated under reducedpressure, and the residue was neutralized with a saturated aqueoussodium carbonate solution and extracted with chloroform (100 ml×3). Thechloroform layer was washed with saturated brine, dried over anhydroussodium sulfate and concentrated under reduced pressure to give a crudeproduct of propyl 5-ethyl-3-pyridinecarboximidate (2.94 g).

The propyl 5-ethyl-3-pyridinecarboximidate were then dissolved inacetonitrile (5 ml), and an aqueous solution (30 ml) of cyanamide (1.13g, 26.9 mmol), Na₂ HPO₄ (1.29 g, 9.1 mmol) and NaH₂ PO₄ ·2H₂ O (8.45 g,54.2 mmol) was added to the solution. The mixture was stirred at roomtemperature for 19 hours. After reaction, the mixture was extracted withchloroform (50 ml×2). The chloroform layer was dried over anhydroussodium sulfate, concentrated under reduced pressure and subjected tosilica gel column chromatography (Wako Gel C-200, 50 g; eluted withhexane:ethyl acetate=5:1) to give 1.51 g (7.0 mmol) of propylN-cyano-5-ethyl-3-pyridinecarboximidate (yield, 44%).

The propyl N-cyano-5-ethyl-3-pyridinecarboximidate (276 mg, 1.27 mmol)thus obtained was next dissolved in methanol (2 ml), and2-(2-chlorophenyl)ethylamine (238 mg, 1.53 mmol) was added to themixture. The resulting mixture was stirred at room temperature for 75minutes. After the completion of the reaction, the mixture wasconcentrated under reduced pressure, and the residue obtained wascrystallized from methanol/diethyl ether to give the title compound (217mg, 0.69 mmol) as colorless crystals (yield, 55%).

Mp 118° C.

IR (KBr) cm⁻¹ : 3230, 2290, 1580.

FD-MS m/z 312 (M, C₁₇ H₁₇ N₄ Cl).

¹ H-NMR (500 Mltz, CDCl₃): δ (ppm) 8.51(1H, s, H-2), 8.43(1H, s, H-6),7.77(1H, s, H-4), 7.4-7.2(4H, C₆ H₄ Cl), 6.56(1H, brs, NH), 3.81(2H, dd,J=6.7, 12.8Hz, NHCH₂ CH₂ C₆ H₄ Cl), 3.15(2H, t, J=6.7Hz, NHCH₂ CH₂ C₆ H₄Cl), 2.70(2H, q, J=7.6Hz, Pyridine-CH₂ CH₃), 1.26(3H, t, J=7.6Hz,Pyridine-CH₂ CH₃).

Example 3 Preparation of 3-Cyano-5-Hydroxymethylpyridine

3-Cyano-B-hydroxymethylpyridine is a well-known compound and may beprepared by the method described in U.S. Pat. No. 5,002,949.

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxymethyl-3-pyridinecarboximidamide

After 3-cyano-5-hydroxymethylpyridine (0.79 g, 5.9 mmol) was dissolvedin 1-propanol (30 ml) and hydrogen chloride gas was passed into thesolution under ice-cooling for 30 minutes, the reactor was tight sealedfor stirring the mixture at room temperature for 20 hours. After thecompletion of the reaction, the reaction mixture was concentrated underreduced pressure, and the residue was neutralized with a saturatedaqueous sodium carbonate solution and extracted with chloroform (30ml×3). The chloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was dissolved inacetonitrile (20 ml), and an aqueous solution (30 ml) of cyanamide (0.50g, 11.9 mmol), Na₂ HPO₄ (0.84. g, 5.9 mmol) and NaH₂ PO₄ ·2H₂ O (3.79 g,23.7 mmol) was added to the solution. The mixture was stirred at roomtemperature for 10 hours. After the completion of the reaction, themixture was extracted with chloroform (100 ml×3). The chloroform layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to give a crude product of propylN-cyano-5-hydroxymethyl-3-pyridinecarboximidate.

The crude product was next dissolved in methanol (10 ml), and2-(2-chlorophenyl)ethylamine (0.5 g, 3.2 mmol) was added to the mixture.The resulting mixture was stirred at room temperature for 3 hours. Afterthe completion of the reaction, the mixture was concentrated underreduced pressure, and the residue obtained was purified by silica gelthin layer chromatography (Merck, No. 5744; developed with chloroform:methanol=10:1) and further crystallized from methanol/diethyl ether togive the title compound (0.12 g, 0.38 mmol) as colorless powder (yieldstarting from 3-cyano-5-hydroxymethylpyridine, 6%).

IR (KBr) cm⁻¹ : 3350, 2200, 1580.

FD-MS m/z 314 (M, C₁₆ H₁₅ N₄ OCl).

¹ H-NMR (90 MHz, CDCl₃):δ (ppm) 8.72(1H, brs, H-6), 8.68(1H, brs, H-2),7.99(1H, m, H-4), 7.4-7.2(4H, C₆ H₄ Cl), 6.82(1H, brs, NH), 4.78(2H, CH₂OH), 3.82(2H, m, NHCH₂ CH₂ C₆ H₄ Cl), 3.12(2H, t, NHCH₂ CH₂ C₆ H₄ Cl).

Example 4 Preparation of 5-carbomethoxy-3-cyanopyridine

3-Cyano-5-ethynylpyridine (1.28 g) (see Example 2) was dissolved inacetone (20 ml), and an aqueous solution (40 ml) of potassiumpermanganate (350 mg) was added dropwise. After the addition wascompleted, the reaction mixture was heated to 100° C. and filtered. Thefiltrate was concentrated under reduced pressure, and the residue wasdissolved in DMF (20 ml). Potassium carbonate (1.6 g) and dimethylsulfate (1 ml) were added to the solution, and the mixture was stirredat room temperature for 10 minutes. Water (10 ml) was added to thereaction mixture, and resulting mixture was extracted with diethyl ether(30 ml×3). The diethyl ether layer was dried over anhydrous sodiumsulfate, concentrated under reduced pressure and purified by silica gelcolumn chromatography (Wako Gel C-200, 10 g; eluted with hexane:diethylether=1:1) to give 5-carbomethoxy-3-cyanopyridine (670 mg; yield, 41%)as colorless solids. IR (KBr) cm⁻¹ : 2210, 1730.

Synthesis of5-carboxy,N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide

After 3-carbomethoxy-5-cyanopyridine (1.2 g, 7.4 mmol) was dissolved in1-propanol (40 ml) and hydrogen. chloride gas was passed into thesolution under icecooling for 20 minutes, the reactor was tight sealedfor stirring the mixture at 0° C. for 22 hours. After reaction, thereaction mixture was concentrated under reduced pressure, and theresidue thus obtained was neutralized with a saturated aqueous sodiumcarbonate solution and extracted with chloroform (50 ml×3). Thechloroform layer, after washing with saturated brine, was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was dissolved in acetonitrile (3 ml), and an aqueous solution(16.5 ml) of cyanamide (682 mg, 16.2 mmol), Na₂ HPO₄ (1.15 g, 8.1 mmol)and NaH₂ PO₄ ·2H₂ O (5.07 g, 32.5 mmol) was added to the solution. Themixture was stirred at room temperature for 18 hours and extracted withchloroform (50 ml x 3). The chloroform layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Wako Gel C-200, 40 g;eluted with hexane:ethyl acetate=3:1) to give 1.39 g (0.56 mmol) ofpropyl N-cyano-5-(3-carbomethoxypyridine)carboximidate (yield, 76%).

IR (KBr) cm⁻¹ :2960, 2180, 1730, 1610, 1280.

FD-MS m/z 247 (M, C₁₂ H₁₃ N₃ O₃).

¹ H-NMR (500 MHz, CDCl₃): δ (ppm) 9.41(1H, d, J=1.8Hz, H-6), 9.39(1H, d,J=1.8Hz, H-2), 8.94(1H, t, J=1.8Hz, H-4), 4.48(2H, t, J=6.4Hz, OCH₂ CH₂CH₃), 4.01(3H, s, COOCH₃), 1.91(2H, m, OCH₂ CH₂ CH₃), 1.08(3H, t,J=7.6Hz, OCH2CH₂ CH₃).

To propyl N-cyano-5-(3-carbomethoxypyridine)-carboximidate (448 mg, 1.81mmol), after dissolved in methanol (10 ml), was added2-(2-chlorophenyl)ethylamine (340 mg, 2.19 mmol), and the mixture wasstirred at room temperature for 105 minutes. After the completion of thereaction, ether (30 ml) was added to the reaction mixture, and whiteprecipitates were collected by filtration and dissolved in methanol (30ml). An aqueous solution of 40% sodium hydroxide (2 ml) was added, andthe mixture was stirred at room temperature for 16 hours. The reactionmixture was neutralized on an acidic ion exchange resin Dowex 50W x8(H+). The resin was removed by filtration, and the filtrate wasconcentrated under reduced pressure to give the title compound (509 mg,yield 86%) as colorless powder.

IR (KBr) cm⁻¹ :3220, 2160, 1590, 1435, 1380, 750.

¹ H-NMR (90 MHz, DMSO): δ (ppm) 9.62(1H, m, NH), 9.16(1H, d, J=1.76Hz,H-2), 8.75(1H, d, J=2.19Hz, H-6), 7.40(1H, dd, J=1.76, 2.19Hz, H-4),7.2-7.2(4H, C₆ H₄ Cl), 3.70(2H, m, NHCH₂ CH2C₆ H₄ Cl), 3.07(2H, t,J=6.82Hz, NHCH₂ CH₂ C₆ H₄ Cl).

Example 5 Preparation of 6-Amino-3-Cyanopyridine

6-Amino-3-cyanopyridine is a well-known compound and may be prepared bythe methods described, for example, in Heterocycles, 22, 1, 117-124(1984); or Journal of Heterocyclic Chemistry, 11, 3, 397-399 (1974).Synthesis of6-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl)-3-pyridinecarboximidamide(N-cyano-N'-[2,(2-chlorophenyl)ethyl]-5-(2-aminopyridine)carboximidamide

After 6-amino-3-cyanopyridine (1.0 g, 8.4 mmol) was dissolved in1-propanol (50 ml) and hydrogen chloride gas was passed into thesolution at a temperature of 0°-10° C. for 30 minutes, the reactor wastight sealed for stirring the mixture at 0° C. for 21 hours. After thecompletion of the reaction, the reaction mixture was concentrated underreduced pressure, and a saturated aqueous sodium hydrogen carbonatesolution (50 ml) was added to the concentrated mixture to adjust the pHto alkaline. The mixture was extracted with chloroform (50 ml×3). Thechloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a crude product of propyl6-amino-3-pyridinecarboximidate (1.56 g).

The crude product was then dissolved in a mixture of acetonitrile (6 ml)and DMF (2 ml), and an aqueous solution (20 ml) NaH₂ PO₄ -2H20 (5.24 g,33.6 mmol), mmol) was added to the solution. The mixture was stirred atroom temperature for 18 hours. After the completion of the reaction,colorless powder deposited was collected by filtration and washed withwater to give propyl N-cyano-6-amino-3-pyridinecarboximidate (1.45 g,yield 85%).

Mp 150° C.

IR (KBr) cm⁻¹ :3380, 2180, 1650, 1580, 1295.

¹ H-NMR (500 MHz, DMSO): δ (ppm). 8.74(1H, d, J=2.4Hz, H-6), 8.04(1H,dd, J=2.4, 9.2Hz, H-4), 7.20(1H, brs, NH₂), 6.53(1H, d, J=9.2Hz, H-3 ) ,4.27 (2H, t, J=6.7Hz, OCH₂ CH₂ CH₃), 1.7 5 (2H, m, OCH₂ CH₂ CH₃) , 0.97(3H, t, J=7.3Hz, OCH₂ CH₂ CH₃). PropylN-cyano-6-amino-3-pyridinecarboximidate (200 mg, 0.98 mmol) and2-(2-chlorophenyl)ethylamine (170 mg, 1.09 mmol) were dissolved in amixture of methanol (10 ml) and DMF (1.5 ml), and the mixture wasstirred at room temperature for 2.5 hours. The reaction mixture wasconcentrated under reduced pressure and subjected to silica gel columnchromatography (Wako Gel C-200, 25 g), and elution was conducted withchloroform:methanol (30:1) to give the title compound (250 mg, yield85%) as colorless powder.

Mp 222° C.

IR (KBr) cm⁻¹ :3220, 2160, 1570, 740.

¹ H-NMR (90 MHz, DMSO): δ (ppm) 8.91(1Hr brs, NH), 8.13(1H, d, J=2.5Hz,H-6), 7.60(1H, dd, J=2.5, 8.6Hz, H-4), 7.45-7.2(4H, C₆ H₄ Cl), 6.60(2H,brs, NH2), 6.48(1H, d, J=8.6Hz, H-3), 3.56(2H, m, NHCH₂ CH₂ C₆ H₄ Cl),3.02(2H, t, J=7.0Hz, NHCH₂ CH₂ C₆ H₄ Cl).

Example 6 Preparation of 5-amino-3-cyanopyridine

5-Amino-3-cyanopyridine is a well-known compound and may be prepared bythe methods described, for example, in Journal of Medicinal Chemistry,10, 2, 149-154 (1967).

Synthesis of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl)-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-(3-aminopyridine)carboximidamide

After 5-amino-3-cyanopyridine (380 mg, 3.19 mmol) was dissolved in1-propanol (15 ml) and hydrogen chloride gas was passed into thesolution at a temperature of 0°-5° C. for 15 minutes, the reactor wastight sealed for stirring the mixture at room temperature for 22 hours.After the completion of the reaction, the solvent was evaporated underreduced pressure, and a saturated aqueous sodium hydrogen carbonatesolution (50 ml) was added to the concentrated mixture to adjust the pHto alkaline. The mixture was extracted with chloroform (50 ml×3). Thechloroform layer was dried over anhydrous sodium sulfate, concentratedunder reduced pressure and subjected to silica gel column chromatography(Wako Gel C-200, 25 g), and elution was conducted with chloroform:methanol (8:1) to give propyl 5-amino-3-pyridinecarboximidate (526 mg,yield 92%) as a colorless oil.

IR (neat) cm⁻¹ :3330, 3200, 1630, 1590, 1080.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.37(1H, brs, H-2), 8.14(1H, d,J=2.6Hz, H-6), 7.31(1H, m, H-4), 4.18(2H, t, J=6.6Hz, OCH₂ CH₂ CH₃),1.77(2H, m, OCH₂ CH₂ CH₃), 1.03(3H, t, J=7.0Hz, OCH₂ CH₂ CH₃).

The propyl 5-amino-3-pyridinecarboximidate (110 mg, 0.6 mmol) was thendissolved in acetonitrile (1 ml), and an aqueous solution (2 ml) of NaH₂PO₄ ·2H₂ O(375 mg, 2.4 mmol), Na₂ HPO₄ (85 mg, 0.6 mmol) and NH₂ CN (50mg, 1.2 mmol) was added to the solution. The mixture was stirred at roomtemperature for 19 hours. After the completion of the reaction, thereaction mixture was extracted with chloroform (20 ml×3), and thechloroform layer was dried over- anhydrous sodium sulfate andconcentrated under reduced pressure to give a crude oil of propyl5-amino-N-cyano-3-pyridinecarboximidate (100 mg, yield 82%).

IR (neat) cm⁻¹ :3350 , 2200, 1610, 1320, 760.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.51(1H, d, J=2.0Hz, H-2) , 8.27(1H, d,J=2.6Hz, H-6), 7.72(1H, dd, J=2.0, 2.6Hz, H-4), 4.39(2H, t, J=6.6Hz,OCH₂ CH₂ CH₃), 4.12(2H, brs, NH₂), 1.83(2H, m, OCH₂ CH₂ CH₃), 1.05 (3H,t, J=7.7Hz, OCH₂ CH₂ CH₃).

To a solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg,0.49 mmol) in methanol (1 ml), 2-(2-chlorophenyl)ethylamine(155 mg, 1.0mmol) was added, and the mixture was stirred at room temperature for 20hours. After the completion of the reaction, the reaction mixture wasconcentrated under reduced pressure, and the residue was crystallizedfrom diethyl ether/ethyl acetate to give the title compound (100 mg,0.33 mmol, yield 68%) as colorless crystals.

Mp 184° C.

IR (neat) cm⁻¹ :3200, 2170, 1570.

FD-MS m/z 299 (M, C₁₅ H₁₄ N₅ Cl).

¹ H-NMR (90 MHz, CD₃ OD): δ (ppm) 8.08(1H, d, J=2.6Hz, H-6), 7.83(1H,brs, H-2) , 7.5-7.2(5H, H-4, C₆ H₄ Cl), 3.73(2H, t, J=7.3Hz , NHCH₂ CH₂C₆ H₄ Cl) , 3.13(2H, t, J=7.3Hz, NHCH₂ CH₂ C₆ H₄ Cl).

Example 7 Synthesis of5-acetamide-N-cyano-N'-[2-(2chlorophenyl)ethy]-3-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-[3-(N-acetylamino)pyridine]carboximidamide

To a solution of5-amino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide(100 mg, 0.33 mmol) in pyridine (1 ml) was added acetic anhydride (20mg, 0.34 mmol), and the mixture was stirred at room temperature for 5.5hours. After the reaction was completed, the reaction mixture was pouredinto ice-water, and precipitates produced was collected by filtration,washed with cold water and crystallized from methanol/diethyl ether togive the title compound (86 mg, yield 75%) as colorless powder.

Mp 230° C.

IR (KBr) cm⁻¹ :3230, 2160, 1700 , 1580 , 720.

FD-MS m/z 341 (M, C₁₇ H₁₆ N₅ OCl).

¹ H-NMR (90 MHz, DMSO): δ (ppm) 10.43(1H, brs, NHCOCH3), 9.41(1H, brs,NH), 8.87(1H, d, J=2.4Hz, H-6), 8.33-1H, d, J=2.0Hz, H-2), 8.24(1H, dd,J=2.0, 2.4Hz, H-4), 7.5-7.3(4H, C₆ H₄ Cl), 3.63 (2H, m, NHCH₂ CH₂ C₆ H₄Cl), 3.08 (2H, t, J=3.2Hz, NHCH₂ CH₂ C₆ H₄ Cl), 2.12(3H, s, NHCOCH₃).

Example 85-Benzamido-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide

To a solution of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(100 mg, 0.33 mmol) in DMF (3 ml) were added triethylamine (101 mg, 1mmol) and benzoyl chloride (94 mg, 0.67 mmol), and the mixture wasstirred at room temperature for 3 hours. After the reaction wascompleted, the reaction mixture was neutralized by adding ice and asaturated aqueous sodium carbonate solution and extracted with ethylacetate. The ethyl acetate layer was washed with saturated brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue thus obtained was purified by silica gel columnchromatography (Wako Gel C-200, 30 g; eluted withchloroform:methanol=200:1) to give the title compound (38 mg, 0.09 mmol,yield 29%).

Mp 220° C.

IR (KBr) cm⁻¹ :3260, 2160, 1655, 1555, 1430.

FD-MS m/z 404 (M, C₂₂ H₁₈ N₅ OCl).

¹ H-NMR (90 MHz, DMSO): δ (ppm) 10.71(1H, brs, NHCOPh) , 9.46(1H, brs,NHCH₂ CH₂ C₆ H₄ Cl), 9.11(1H, d, J=2.2Hz, H-6), 8.5-8.3(2H, H-2, H-4),8.1-7.3(9H, Ph, C₆ H₄ Cl) 3.63(2H, m, NHCH₂ CH₂ C₆ H₄ Cl) , 3.08(2H, t,J=7.2Hz, NHCH₂ CH₂ C₆ H₄ Cl).

Example 9 Preparation of 3-cyano-5-dimethylaminopyridine

To a solution of 5-amino-3-cyanopyridine (0.50 g, 4.20 mmol) in DMF (5ml) was added NaH (60% in oil) (0.37 g, 9.26 mmol) under ice-cooling,and the mixture was stirred for 20 minutes. Methyl iodide (0.58 ml, 9.31mmol) in DMF (2 ml) was added dropwise under ice-cooling. The mixturewas stirred for 2 hours while the temperature was raised up to roomtemperature. Ice was added to the reaction mixture, and the mixture wasextracted with diethyl ether (30 ml×3). The diethyl ether layer waswashed with saturated brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography (Wako Gel C-200, 20 g;eluted with chloroform:methanol=200:1) to give3-cyano-5-dimethylaminopyridine (145 mg, yield 23%).

Mp 104° C.

IR (KBr) cm⁻¹ :2230, 1595, 1450, 1375, 1235, 695.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.28(1H, d, J=3.1Hz, H-6), 8.18(lH, d,J=1.5Hz, H-2), 7.09(1H, dd, J=1.5, 3.1Hz, H-4), 3.03(6H, s, N(CH₃)₂).

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-dimethylamino-3-pyridinecarboximidamide

Into a solution of 3-cyano-5-dimethylaminopyridine (140 mg, 0.95 mmol)in 1-propanol (15 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at room temperature for 20 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure,and the residue was neutralized with sodium carbonate and extracted withchloroform (50 ml×3). The chloroform layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue wasdissolved in acetonitrile (5 ml) and an aqueous solution (10 ml) ofcyanamide (80 mg, 1.9 mmol), Na₂ HPO₄ (135 mg, 0.95 mmol) and NaH₂ PO₄·2H₂ O (593 mg, 3.80 mmol) was added to the solution. The mixture wasstirred at room temperature for 10 hours. After the reaction wascompleted, the reaction mixture was extracted with chloroform (30 ml),and the chloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a pale yellow syrup.

To a solution of this syrup dissolved in methanol (10 ml) was added2-(2-chlorophenyl)ethylamine (170 mg, 1.09 mmol), and the mixture wasstirred at room temperature for 4 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure,and the residue was purified by silica gel column chromatography (WakoGel C-200, 20 g; eluted with chloroform:methanol=100:1) and furthercrystallized from methanol/diethyl ether to give the title compound (219mg, 0.67 mmol) in the yield of 70%.

Mp 158° C.

IR (KBr) cm⁻ :3400, 2160, 1575, 1430.

FD-MS m/z 327 (M, C₁₇ H₁₈ N₅ Cl).

¹ H-NMR (90 MHz, DMSO): δ (ppm) 9.25(1H, brs, NHCH₂ CH₂ C₆ H₄ Cl),8.26(1H, d, J=2.9Hz, H-6), 7.95(1H, d, J=1.8Hz, H-2), 7.5-7.2(4H, C₆ H₄Cl), 7.11(1H, dd, J=1.8, 2.9Hz, H-4), 3.63(2H, m, NHCH₂ CH₂ C₆ H₄ Cl),3.05(2H, m, NHCH₂ CH₂ C₆ H₄ Cl), 2.98(6H, s, N(CH₃)₂).

Example 10 Preparation of 3-Cyano-5-Ethylaminopyridine

To a solution of 5-amino-3-cyanopyridine (300 mg, 2.52 mmol) in methanol(10 ml) was added acetaldehyde (1.42 ml, 25.1 mmol), and the mixture wasstirred at room temperature for 10 minutes. Next, sodiumcyanoborohydride (950 mg, 15.1 mmol) was added, and acetic acid wasfurther added to adjust the pH of thereaction mixture to about 6. Themixture was stirred for 5 hours. After the reaction was completed, thereaction mixture was neutralized with an aqueous sodium carbonatesolution and extracted with diethyl ether (30 ml×3). The diethyl etherlayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue thus obtained was purified by silica gelcolumn chromatography (Wako Gel C-200, 20 g; eluted withchloroform:methanol=200:1) to give 3-cyano-5-ethylaminopyridine (200 mg,1.36 mmol, yield 54%).

Mp 110° C.

IR (neat) cm⁻¹ :2210, 1585, 1450, 1180, 690.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.2-8.1(2H, H-2, H-6), 6.99(1H, dd,J=1.8, 2.9Hz, H-4), 4.08(1H, brs, NH), 3.61(2H, m, NHCH₂ CH₃), 1.25(3H,d, J=6.4Hz, NHCH₂ CH₃).

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-ethylamino-3-pyridinecarboximidamid

Into a solution of 3-cyano-5-ethylaminopyridine (380 mg, 2.59 mmol) in1-propanol (40 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at room temperature for 20 hours and concentrated under reducedpressure. After the residue was neutralized with a saturated aqueoussodium carbonate solution and extracted with chloroform (50 ml×3). Thechloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a crude product of propyl5-ethylamino-3-pyridinecarboximidate. The crude product was thendissolved in acetonitrile (5 ml) and an aqueous solution (18 ml) ofcyanamide (210 mg, 5.0 mmol), Na₂ HPO₄ (355 mg, 2.5 mmol) and NaH₂ PO₄·2H₂ O (1.56 g, 10 mmol) was added to the solution, and the mixture wasstirred at room temperature over night. After the reaction wascompleted, the reaction mixture was extracted with chloroform (30 ml×3),and the chloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue obtained was purifiedby silica gel column chromatography (Wako Gel C-200, 30 g; eluted withhexane/ethyl acetate) to give propylN-cyano-5-ethylamino-3-pyridinecarboximidate (322 mg, 1.38 mmol) as acolorless oil (Yield 54%).

IR (KBr) cm⁻¹ :2960, 2200, 1600, 1460, 1330.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.41(1H, d, J=2.0Hz, H-6), 8.18(1H, d,J=2.9Hz, H-2), 7.61(1H, dd, J=2.0, 2.9Hz, H-4), 4.39(2H, t, J=6.5Hz,OCH₂ CH₂ CH₃), 3.95(1H, brs, NH), 3.22(2H, m, NHCH₂ CH₃), 1.82(2H, m,OCH₂ CH₂ CH₃), 1.31(3H, t, J=7.2Hz, NHCH₂ CH₃), 1.06(3H, t, J=6.8Hz,OCH₂ CH₂ CH₃).

To a solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (98mg, 0.42 mmol) in methanol (3 ml) was added2-(2-chlorophenyl)ethylamine(79 mg, 0.51 mmol), and the mixture wasstirred for 105 minutes. The residue obtained by concentration underreduced pressure was purified by silica gel column chromatography (WakoGel C-200, 30 g; eluted with chloroform:methanol=100:1) and furthercrystallized from diethyl ether to give the title compound (110 mg, 0.34mmol) as colorless crystals in the yield of 80%.

Mp 168° C.

IR (KBr) cm⁻¹ :3230, 2170, 1560, 1445, 750.

FD-MS m/z 327 (M, C₁₇ H₁₈ N₅ Cl).

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 7.95(1H, d, J=2.6Hz, H-6), 7.79(1H, d,J=1.8Hz, H-2), 7.4-7.0(5H, H-4, C₆ H₄ Cl), 4.35(1H, brs, NHCH₂ C₆ H₄Cl), 3.76(2H, m, NHCH₂ CH₂ C₆ H₄ Cl), 3.3-2.9(4H, NHCH₂ CH₂ C₆ H₄ Cl,NHCH₃), 2.88(1H, brs, NHCH₂ CH₃), 1.26(3H, t, J=7.1Hz, NHCH₂ CH₃).

Example 11 Preparation of 3-Cyano-5Isopropylaminopyridine

In the similar manner as in the preparation of3-cyano-5-ethylaminopyridine, 3-cyano-5-isopropylaminopyridine wasobtained.

Mp 82° C.

IR (neat) cm⁻¹ :2210, 1585, 1450, 1180, 690.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.2-8.1(2H, H-2, H-6), 6.99(1H, dd,J=1.8, 2.9Hz, H-4), 4.08(1H, brs, NH), 3.61(1H, m, NHCH(CH₃)₂), 1.25(6H,d, J=6.4Hz, NHCH(CH₃)₂).

N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-isopropylamino-3-pyridinecarboximidamide

Into a solution of 3-cyano-5-isopropylaminopyridine (118 mg, 0.73 mmol)in 1-propanol (20 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at room temperature for 17 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure,and the residue was neutralized with a saturated sodium carbonatesolution and extracted with chloroform (50 ml×3). The chloroform layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to give a yellow syrup. To the syrup was then added an aqueoussolution (6 ml) of cyanamide (61 mg, 1.45 mmol), Na₂ HPO₄ (104 mg, 0.73mmol) and NaH₂ PO₄ ·2H₂ O (456 mg, 2.92 mmol), and the mixture wasstirred at room temperature for 22 hours. After the reaction wascompleted, the reaction mixture was extracted with chloroform (30 ml×3),and the chloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give propylN-cyano-5-isopropylamino-3-pyridinecarboximidate (80 mg, 0.33 mmol) as ayellow syrup (Yield 44%).

IR (neat) cm⁻¹ :2950, 2180, 1580, 1445, 1310.

¹ H-NMR (500 MHz, CDCl₃): δ (ppm) 8.38(1H, d, J=1.8Hz, H-6), 8.16(1H, d,J=3.1Hz, H-2), 7.58(1H, dd, J=1.8, 3.1Hz, H-4), 4.38(2H, t, J=6.4Hz,OCH₂ CH₂ CH₃), 4.09(1H, brs, NH), 3.66(1H, m, NHCH(CH₃)₂), 1.86 (2H, m,OCH₂ CH₂ CH₃), 1.26 (6H, d, J=6.1Hz, NCH(CH₃)₂), 1.05(3H, t, J=7.3Hz ,OCH₂ CH₂ CH₃).

To a solution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate(98 mg, 0.42 mmol) in methanol (3 ml) was added2-(2-chlorophenyl)ethylamine (79 mg, 0.51 mmol), and the mixture wasstirred for 105 minutes. After the reaction was completed, the reactionmixture was concentrated under reduced pressure and the residue obtainedwas purified by silica gel column chromatography (Wako Gel C-200, 30 g;eluted with chloroform:methanol=100:1) and further crystallized fromdiethyl ether to give the title compound (110 mg, 0.34 mmol) ascolorless crystals in the yield of 80%.

IR (KBr) cm⁻ :2960, 2160, 1555, 1440.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 7.98(1H, d, J=2.6Hz, H-6), 7.78(1H, d,J=1.8Hz, H-2), 7.5-7.2(4H, C₆ H₄ Cl), 7.12(1H, dd, J=1.8, 2.6Hz, H-4),6.62(1H, brt, NHCH₂ CH₂ C₆ H₄ Cl), 4.11(1H, NHCH(CH₃)₂), 3.76(2H, m,NHCH₂ CH₂ C₆ H₄ Cl), 3.46(1H, m, NHCH(CH₃)₂), 3.14(2H, t, J=6.6Hz, NHCH₂CH₂ C₆ H₄ Cl), 1.24(6H, d, J=6.4Hz, NHCH(CH₃)₂).

Example 12 Preparation of 5-N-Butylamino-3-Cyanopyridine

In the similar manner as in the preparation of3-cyano-5-ethylaminopyridine , 5-n-butylamino-3-cyanopyridine wasobtained.

Mp 73° C.

IR (KBr) cm⁻¹ :3270, 2240, 1590, 1440, 690.

¹ H-NMR (90MHz, CDCl₃): δ (ppm) 8.2-8.1(2H, H-2, H-6), 6.99(1H, dd,J=2.0, 2.6Hz, H-4), 3.96(1H, brs, NH), 3.13(2H, m, NHCH₂ CH₂ CH₂ CH₃),1.6-1.3(4H, NHCH₂ CH₂ CH₂ CH₃), 0.98(3H, t, J=6.4Hz, NHCH₂ CH₂ CH₂ CH₃).

Synthesis of5-n-butylamino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide

Into a solution of 5-n-butylamino-3-cyanopyridine (255 mg, 1.46 mmol) in1-propanol (30 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at-room temperature for 16 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure,and the residue was neutralized with a saturated aqueous sodiumcarbonate solution and extracted with chloroform (50 m×3). Thechloroform layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a syrup.

To a solution of the syrup in acetonitrile (3 ml) was then added anaqueous solution (20 ml) of cyanamide (123 mg, 2.93 mmol), Na₂ HPO₄ (207mg, 1.46 mmol) and NaH₂ PO₄ ·2H₂ O (911 mg, 5.84 mmol), and the mixturewas stirred at room temperature for 22 hours. The reaction mixture wasextracted with chloroform (30 ml×3), and the chloroform layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (Wako GelC-200, 30 g; eluted with hexane:ethyl acetate=4:1) to give propyl5-n-butylamino-N-cyano-3-pyridinecarboximidate (252 mg, 0.97 mmol) as ayellow syrup.

IR (neat) cm⁻¹ :2950, 2170, 1590, 1460, 1320.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.40(1H, d, J=2.0Hz, H-6), 8.19(1H, d,J=2.9Hz, H-2), 7.57(1H, dd, J=2.0, 2.9Hz, H-4), 4.39(2H, t, J=6.6Hz,OCH₂ CH₂ CH₃), 3.16(2H, m, NHCH₂ CH₂ CH₂ CH₃), 2.0-1.2 (6H, 3×CH₂),1.1-0.8(6H, 2×CH₃).

To a solution of propyl 5-n-butylamino-N-cyano-3-pyridinecarboximidate(99 mg, 0.38 mmol) in methanol (2 ml) was added2-(2-chlorophenyl)ethylamine (71 mg, 0.46 mmol), and the mixture wasstirred for 2 hours. After the reaction was completed, the reactionmixture was concentrated under reduced pressure and the residue obtainedwas purified by silica gel column chromatography (Wako Gel C-200, 30 g;eluted with chloroform:methanol=200:1) and further crystallized fromdiethyl ether to give the title compound (90 mg, 0.25 mmol) as colorlesscrystals in the yield of 67%.

Mp 122° C.

IR (KBr) cm⁻¹ :2950, 2160, 1560, 1460, 750.

FD-MS m/z 355 (M, C₁₉ H₂₂ N₅ Cl).

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 7.92(1H, d, J=2.6Hz, H-6), 7.77(1H, d,J=1.8Hz, H-2), 7.5-7.1(4H, C6H4C1), 7.07(1H, dd, J=1.8, 2.6Hz, H-4),4.46(1H, brt, NH), 3.75(2H, m, NHCH₂ C₆ H₄ Cl), 3.2-2.8(4H, 2×CH₂),1.7-1.2(4H, 2×CH₂), 0.95(3H, t, J=6.8Hz, CH₃).

Example 13 Preparation of 5-Benzylamino-3-Cyanopyridine

In the similar manner as in the preparation of3-cyano-5-ethylaminopyridine, 5-benzylamino-3-cyanopyridine wasobtained.

Mp 131° C.

IR (KBr) cm⁻¹ :3220, 2220, 1610, 1580, 700.

¹ H-NMR (90 MHz, CD₃ OD): δ (ppm) 8.36(1H, d, J=1.5Hz, H-2), 8.23(1H, d,J=2.9Hz, H-6), 7.91(1H, dd, J=1.5, 2.9Hz, H-4), 7.5-7.2(5H, CH₂ Ph),4.48(2H, s, CH₂ Ph).

Synthesis of5-Benzylamino-N-Cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide

Into a solution of 5-benzylamino-3-cyanopyridine (250 mg, 1.19 mmol) in1-propanol (30 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at room temperature for 16 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure,and the residue was neutralized with an aqueous sodium carbonatesolution and extracted with chloroform (50 ml×3). The chloroform layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure.

To the solution of the residue in acetonitrile (2 ml) was then added anaqueous solution (20 ml) of cyanamide (100 mg, 2.38 mmol), Na₂ HPO₄ (170mg, 1.20 mmol) and NaH₂ PO₄ ·2H₂ O (743 mg, 4.76 mmol), and the mixturewas stirred at room temperature for 24 hours. The reaction mixture wasextracted with chloroform (50 ml×3), and the chloroform layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (Wako GelC-200, 30 g; eluted with hexane:ethyl acetate=4:1) to give propyl5-benzylamino-N-cyano-3-pyridinecarboximidate (206 mg, 0.7 mmol) as asyrup.

To a solution of propyl 5-benzylamino-N-cyano-3-pyridinecarboximidate(114 mg, 0.38 mmol) in methanol (2 ml) was added2-(2-chlorophenyl)ethylamine (72 mg, 0.46 mmol), and the mixture wasstirred for 105 minutes. After the reaction was completed, the reactionmixture was concentrated under reduced pressure and the residue obtainedwas purified by silica gel column chromatography (Wako Gel C-200, 20 g;eluted with chloroform:methanol=200:1) and further crystallized fromdiethyl ether to give the title compound (126 mg, 0.32 mmol) ascolorless crystals in the yield of 85%.

Mp 146° C.

IR (KBr) cm⁻¹ :2180, 1560, 1445, 750.

FD-MS m/z 389 (M, C₂₂ H₂₀ N₅ Cl).

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 7.94(1H, d, J=2.6Hz, H-6), 7.82(1H, d,J=1.8Hz, H-2), 7.4-7.0(10H), 4.92(1H, brs, NH), 4.29(2H, brd, J=5.5Hz,NHCH₂ Ph), 3.8-3.6(3H, NH, NHCH₂ CH₂ C₆ H₄ Cl), 3.09(2H, t, J=6.6Hz,NHCH₂ CH₂ C₆ H₄ Cl).

Example 14

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-methanesulfonamido-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-[3-(N-methanesulfonylamino)pyridine]-carboximidamide)

To a solution of5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide(110 mg, 0.39 mmol) in pyridine (2 ml) was added anhydrousmethanesulfonic acid (65 mg, 0.37 mmol), and the mixture was stirred atroom temperature for 5 hours. After the reaction was completed, ice anda saturated aqueous sodium carbonate solution (20 ml) were added to thereaction mixture, and the mixture was extracted with ethyl acetate (30ml×3). The ethyl acetate layer was washed with saturated brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was subjected to silica gel column chromatography(Wako Gel C-200, 20 g) and eluted with chloroform:methanol (50:1) togive the title compound (45 mg, yield 32%) as colorless powder.

Mp 205° C.

IR (KBr) cm⁻ :3400, 2150, 1590, 1555, 1150.

FD-MS m/z 378 (M+1, C₁₆ H₁₆ N₅ O₂ SCl).

¹ H-NMR (90 MHz, DMSO): δ (ppm) 10.42(1H, brs, NHSO₂ CH₃), 9.46(1H, brs,NH), 8.87(1H, d, J=2.4Hz, H-6), 8.39(1H, d, J=2.0Hz, H-2), 7.76(1H, dd,J=2.0, 2.4Hz, H-4), 7.5-7.3(4H, Ph), 3.66(5H, NHCH₂ CH2Ph, NHSO₂ CH₃),3.16(2H, NHCH₂ CH₂ Ph).

Example 15

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-bis(methanesulfonylamino)-3-pyridinecarboximidamide(N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-[3-(N,N-bismethanesulfonylamino)pyridine]carboximidamide)

To a solution of5-amino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide(108 mg, 0.36 mmol) in a mixture of acetonitrile (1 ml) and DMF (1 ml)was added triethylamine (144 mg, 1.43 mmol) and methanesulfonyl chloride(88 mg, 0.77 mmol), and the mixture was stirred at room temperature for2.5 hours. After the reaction was completed, the reaction mixture waspoured into ice and saturated brine and extracted with ethyl acetate (30ml×3). The ethyl acetate layer was washed with saturated brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue obtained was subjected to silica gel column chromatography(Wako Gel C-200, 20 g) and eluted with chloroform:methanol (100:1) togive the title compound (89 mg, yield 54%) as colorless powder.

Mp 210° C.

IR (KBr) cm⁻¹ :3230, 2160, 1580.

¹ H-NMR (90 MHz, DMSO): δ (ppm) 9.60(1H, brs, NH), 8.94(1H, d, J=2.4Hz,H-6), 8.83(1H, d, J=1.8Hz, H-2), 8.23(1H, dd, J=1.8, 2.4Hz, H-4),7.4-7.2(4H, Ph), 3.83(8H, 2×NHSO₂ CH₃ , NHCH₂ CH₂ Ph), 3.08(2H, t,J=7.8Hz, NHCH₂ CH₂ Ph).

Example 16 Synthesis of5-amino-N-cyano-N'-(2-phenethyl)-3-pyridinecarboximidamide

To a solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (310 mg,1.51 mmol) in methanol (5 ml) was added phenethylamine (230 mg, 1.90mmol), and the mixture was stirred at room temperature for 2 hours.After the reaction was completed, the reaction mixture was concentratedunder reduced pressure and the residue was crystallized frommethanol/diethyl ether to give the title compound (222 mg, 0.84 mmol) aspale yellow crystals (Yield 56%).

Mp 158° C.

IR (KBr) cm⁻¹ :3200, 2160, 1580, 1550, 1430. ¹ H-NMR (90 MHz, DMSO): δ(ppm) 9.21(1H, brd, NH), 8.07(1H, d, J=2.6Hz, H-6), 7.76(1H, d, J=2.0Hz,H-2), 7.4-7.2(5H, Ph), 7.00(1H, dd, J=2.0, 2.6Hz, H-4), 5.70(2H, brs,NH₂), 3.58(2H, m, NHCH₂ CH₂ Ph), 2.88(2H, t, J=6.9Hz, NHCH₂ CH₂ Ph).

Example 17 Preparation of 3-Cyano-5-Hydroxypyridine

5-Hydroxynicotinamide (0.69 g, 5 mmol) prepared by the method describedin International Patent Publication No. 8606628 was dissolved inpyridine (50 ml). Trifluoroacetic anhydride (2.52 g, 12 mmol) was added,and the mixture was stirred at 0° C. for 20 hours. The reaction mixture,to which water (20 ml) was added, was concentrated under reducedpressure and extracted with chloroform (50 ml×3). The chloroform layerwas washed with water (50 ml), dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give a residue. The residue waspurified by silica gel column chromatography (Wako Gel C-200, 20 g;eluted with chloroform:methanol=100:1) to give 3-cyano-5-hydroxypyridine(0.42 g, 3.5 mmol) (Yield 70%).

IR (neat) cm⁻¹ :3250, 2920, 2180.

¹ H-NMR (90 MHz, CDCl₃ -CD₃ OD): δ (ppm) 8.86(1H, d, J=1.9Hz, H-2),8.40(1H, d, J=2.5Hz, H-6), 7.42(1H, dd, J=1.9, 2.5Hz, H-4).

Synthesis ofN-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxy-3-pyridinecarboximidamide

Into a solution of 3-cyano-5-hydroxypyridine (0.42 g, 3.50 mmol) in1-propanol (40 ml) was passed hydrogen chloride gas under ice-coolingfor 30 minutes. The reactor was tight sealed, and the mixture wasstirred at room temperature for 20 hours. After the reaction wascompleted, the reaction mixture was concentrated under reduced pressure.To the solution of the residue in acetonitrile (20 ml) was then added anaqueous solution (30 ml) of cyanamide (0.88 g, 20.9 mmol), Na₂ HPO₄ (1.5g, 10.6 mmol) and NaH₂ PO₄ ·2H₂ O (3.27 g, 21.0 mmol), and the mixturewas stirred at room temperature for 6 hours. The reaction mixture wasadjusted to pH 7.0 with a saturated aqueous sodium hydrogen carbonatesolution and extracted with chloroform (50 ml×3). The chloroform layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to give a crude product of propylN-cyano-5-hydroxy-3-pyridinecarboximidate (0.26 g).

To a solution of propyl N-cyano-5-hydroxy-3-pyridinecarboximidate (0.26g) in methanol (5 ml) was added 2-(2-chlorophenyl)ethylamine (0.22 g,1.4 mmol), and the mixture was stirred for 4 hours. After the reactionwas completed, the reaction mixture was concentrated under reducedpressure and the residue obtained was extracted with chloroform (50ml×3). The chloroform layer was washed with water (100 ml), dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (Wako GelC-200, 30 g; eluted with chloroform:methanol=50:1) and furthercrystallized from diethyl ether to give the title compound (0.16 g, 0.53mmol) as colorless crystals. (Yield starting from3-cyano-5-hydroxypyridine 15%).

IR (KBr) cm⁻¹ :3250, 2200, 1590.

FD-MS m/z 300 (M, C₁₅ H₁₃ N₄ OCl).

¹ H-NMR (90 MHz, CD₃ OD): δ (ppm) 8.35(1H, d, J=1.8Hz, H-6), 8.22(1H,J=2.6Hz, H-2), 7.54(1H, dd, J=1.8, 2.6Hz , H-4) , 7.4-7.1(4H, C₆ H₄ Cl),3.70(2H, m, NHCH₂ CH₂ C₆ H₄ Cl), 3.08 (2H, t, J=7.3Hz, NHCH₂ CH₂ C₆ H₄Cl).

Example 18 (Tablet/in 1 Tablet)

    ______________________________________                                        5-Amino-N-cyano-N'-       2 mg                                                [2-(2-chlorophenyl)ethyl]-                                                    3-pyridinecarboximidamide                                                     (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-                                        5-(3-aminopyridine)carboximidamide)                                           Lactose                   75.5 mg                                             Maize starch              18 mg                                               Talc                      4 mg                                                Sodium stearate           0.5 mg                                              Total                     100 (mg)                                            ______________________________________                                    

The aforementioned ingredients are mixed and pressed into a tablet.

Example 19 (Capsule/in 1 Capsule)

    ______________________________________                                        5-Amino-N-cyano-N'-[2-    5 mg                                                (2-chlorophenyl)ethyl]-3-                                                     pyridinecarboximidamide                                                       (N-cyano-N'-[2-(2-chlorophenyl)ethyl]-                                        5-(3-aminopyridine)carboximidamide)                                           Lactose                   94 mg                                               Sodium stearate           1 mg                                                Total                     100 (mg)                                            ______________________________________                                    

The aforementioned ingredients are mixed and capsuled to form a capsule.

(2) When R³ in the formula (I) represents a nitroxyl group:

Pharmacological Test 1: Vasodilating effect in a rat aorta

(1) Test Method

Physiological effect of the compound of the present invention was testedby the method with use of an isolated rat aorta.

Thoracic aorta was isolated from a male Wistar rat (body weight, 250-350g) exsanguinated to death for obtaining ring preparations having a widthof 3 mm. The preparations were suspended into an organ bath filled withthe Krebs-Ringer solution through which a mixed gas of 95% O₂ and 5% CO₂had been aerated at 37° C. A resting tension of 1 g was applied to thepreparation. After the tension in the preparation was stabilized, thesolution in the organ bath was exchanged with an equimolar solutioncontaining 40 mM KC1 to increase the tension of the preparation. Whenthe tension induced by KCl become stable, the test compound wascumulatively added to the organ bath to relax the preparation.Relaxation response was expressed as percentage inhibition ofKCl-induced contraction, and the IC₅₀ value (concentration forinhibiting 50% of the tension induced by KCl) was calculated from theaverage concentration-response curve by the Probit method.

(2) Results

The IC₅₀ values of the representative compounds among the compounds ofthe present invention are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Compound No.    IC.sub.50 (M)                                                 ______________________________________                                        (18)            2.2 × 10.sup.-5                                         (19)            1.0 × 10.sup.-5                                         (20)            2.7 × 10.sup.-6                                         (21)            4.6 × 10.sup.-6                                         ______________________________________                                    

Pharmacological Test 2: Antihypertensive Effects on SHR

Antihypertensive effects of-5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide(N-cyano-N'-(2-nitroxyethyl)-5-(3-aminopyridine)carboximidamide;Compound No. 18) andN-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide(N-cyano-N'-(2-nitroxyethyl)-5-[3-(N-ethylaminopyridine)]carboximidamide;Compound No. 19) were assessed by comparison with those of themethanesulfonate salt ofN-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (compounddescribed in Japanese Patent Laid-Open Publication No. 163061/1991) as areference compound which is thought to be a well-known compound mostsimilar to the compound of the present invention.

(1) Test Method

Antihypertensive effects of the compound of the present invention wereobserved with conscious male spontaneously hypertensive rats (SHR).Systolic blood pressure (SBP) was measured with the tail cuff method.

Each of the compound Nos. 18 and 19 was dissolved in an equivalentmixture of polyethylene glycol 200 and physiological saline, and thereference compound was dissolved in physiological saline. The compoundswere administered orally with the aid of an oral probe. SBP was measuredbefore administration and 1, 2, 4, 6, 8, 12 and 24 hours afteradministration of the compound. The results were expressed as thepercentage change in SBP observed before administration.

(2) Results

The decrease in blood pressure was observed on the administration of 3.0mg/kg of Nos. 18 and 19. Antihypertensive effect induced by both drugslasted for 12 hours or more (see Table 2). On the other hand,antihypertensive effect was also observed at the dose of 3.0 mg/kg ofthe reference compound but lasted for about 6 hours (see Table 2). Table2: Antihypertensive effects of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (CompoundNo. 18),N-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide(Compound No. 19) andN-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonicacid (Reference Compound) on SHR (Data are expressed as the percentchange in SBP observed before administration of the compound)

    __________________________________________________________________________               Time after administration (hour)                                   Compound No.                                                                             1   2   4   6   8   12  24                                         __________________________________________________________________________    Reference Compound                                                                       -55.9                                                                             -41.5                                                                             -10.6                                                                             -6.8                                                   18         -56.9                                                                             -49.2                                                                             -42.6                                                                             -17.9                                                                             -20.5                                                                             -22.2                                                                             -3.7                                       19         -60.2                                                                             -47.2                                                                             -24.3                                                                             -23.9                                                                             -25.9                                                                             -27.7                                                                             -9.8                                       __________________________________________________________________________     Pharmacological Test 3: Coronary dilating effect of     5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (Compound     No. 18) on beagles

Coronary dilating effects of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (CompoundNo. 18) of the present invention was assessed by comparison with thoseof N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonicacid (compound described in Japanese Patent Laid-Open Publication No.163061/1991) which is thought to be a well-known compound most similarto the compound of the present invention.

(1) Test Method

A dog (body weight, 8.3 kg) was anesthetized with 30 mg/kg ofpentobarbital sodium intravenously. Respiration was maintained with roomair through a cuffed endotracheal tube. The drug was administeredthrough the femoral vein, and the coronary blood flow was measured by aprobe attached to the circumflex branch of the left coronary artery.

(2) Results

When 5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide(Compound No. 18) was administered intravenously in a dose of 10 Mg/Kg,and increase of coronary blood flow was observed and retained for 15minutes or more. While the increase in coronary blood flow was observedwith N-cyano-N'-(2-nitroxyethyl)3-pyridinecarboximidamidemethanesulfonic acid (Reference Compound) in a dose of 10 Mg/Kg, it wasretained only 10 minutes or less. Table 3: Effects of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (CompoundNo. 18) and N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamidemethanesulfonic acid (Reference Compound) administered intravenously ina dose of 10 Mg/Kg on coronary blood flow (anesthetized dog) (Data areexpressed as percent change as compared with the blood flow beforeadministration of the compound)

    ______________________________________                                                   Time after dosage (min)                                            Compound No. 1       3      5     10   15   20                                ______________________________________                                        18           200.0   123.8  71.4  19.0 19.0 0.0                               Reference compound                                                                         219.0   42.9   14.3  0.0                                         ______________________________________                                    

Pharmacological Test 4: Acute Toxicity

Acute toxicity of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (CompoundNo. 18) of the present invention on oral administration was examinedwith male SD rats (5 weeks old). As a result, LD₅₀ was about 600 mg/kg.

Example 1 Preparation of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide

To a solution of 2-nitroxyethylamine hydrochloride (140 mg, 0.98 mmol)in DMF (1 ml) was added sodium methoxide (42 mg, 0.78 mmol) followed bya solution of propyl 5-amino-N-cyano-3-pyridinecarboximidate (100 mg,0.49 mmol) in methanol (1 ml) described in Example 6 of ExperimentalExample 1, and the mixture was stirred at room temperature for 3 hours.After the reaction was completed, the reaction mixture was evaporatedunder reduced pressure. The residue was suspended in water and extractedwith chloroform. The chloroform layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography with a mixedsolvent of methanol and chloroform as an eluent to give the titlecompound (77 mg, yield 63%) as colorless crystals.

Mp 121° C.

IR (KBr) cm⁻¹ :3230, 2160, 1640, 1570, 1280.

¹ H-NMR (90 MHz, CD₃ OD): δ (ppm) 8.12(1H, d, J=2.6Hz), 7.93(1H, d,J=2.0Hz), 7.24(1H, dd, J=2.6, 2.0Hz), 4.74(2H, t, J=5.2Hz), 3.80(2H, t,J=5.2Hz).

MS 250 (M+), 188 [(M-ONO₂)⁺ ].

Example 2 Preparation ofN-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide

To a solution of 2-nitroxyethylamine hydrochloride (659 mg, 4.62 mmol)in DMF (1 ml) was added sodium methoxide (227 mg, 4.20 mmol) followed bya solution of propyl N-cyano-5-ethylamino-3-pyridinecarboximidate (195mg, 0.84 mmol) in DMF (1 ml) described in Example 10 of ExperimentalExample 1, and the mixture was stirred at room temperature for 3 hours.After the reaction was completed, the reaction mixture was evaporatedunder reduced pressure. The residue was suspended in water and extractedwith chloroform. The chloroform layer was dried over anhydrous sodiumsulfate and concentrated under redeuced pressure. The residue thusobtained was purified by silica gel column chromatography with a mixedsolvent of methanol and chloroform as an eluent to give the titlecompound (208 mg, yield 89%) as colorless crystals.

Mp 100° C.

IR (KBr) cm⁻¹ :3230, 2170, 1630, 1550, 1275.

¹ H-NMR (90 MHz, CDC13): δ (ppm) 8.28(1H, brt), 7.97(1H, d, J=2.6Hz),7.89(1H, J=1.8Hz), 7.12(1H, dd, J=2.6, 1.8Hz), 4.70(2H, t, J=5.0Hz),3.83(2H, m), 3.15(2H, m), 1.25(3H, t, J=7.2Hz).

MS 278 (M⁺), 216 [(M-ONO₂)⁺ ].

Example 3 Preparation of6-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide

To a solution of 2-nitroxyethylamine hydrochloride (1.36 g, 9.54 mmol)in DMF (3.5 ml) was added sodium methoxide (470 mg, 8.7 mmol) followedby a solution of propyl N-cyano-6-amino-3-pyridinecarboximidate (355 mg,1.74 mmol) in DMF (2 ml) described in Example 5 of Experimental Example1, and the mixture was stirred at room temperature for 3 hours. Afterthe reaction was completed, the reaction mixture was evaporated underreduced pressure. The residue was suspended in water and extracted withchloroform. The chloroform layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue thus obtained waspurified by silica gel column chromatography with a mixed solvent ofmethanol and chloroform as an eluent to give the title compound (284 mg,yield 74%) as colorless crystals.

Mp 108° C.

IR (KBr) cm⁻¹ :3230, 2160, 1640, 1570, 1280.

¹ H-NMR (90 MHz, DMSO): δ (ppm) 9.00(1H, brt), 8.23(1H, dd, J=2.42,0.66Hz), 7.66(1H, dd, J=8.79,- 2.64Hz), 6.72(2H, brs), 6.50(1H, dd,J=8.79, 0.88Hz), 4.70(2H, t, J=5.27Hz), 3.66(2H, m).

MS 250 (M⁺), 188 [(M-ONO₂)⁺ ].

Example 4 Preparation ofN-cyano-6-diethylamino-N'-(2-nitroxyethyl),3-pyridinecarboximidamide

To a solution of 6-chloro-3-cyanopyridine (500 mg, 3.60 mmol) in DMF (5ml) were added potassium carbonate (500 mg, 3.62 mmol), sodium iodide(catalytic amount) and diethylamine (400 mg, 5.50 mmol), and the mixturewas stirred at 120° C. for 3 hours. The reaction mixture, to which water(5 ml) was added, was extracted with ethyl acetate. The ethyl acetatelayer was washed with a saturated brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography with a mixedsolvent of ethyl acetate and hexane as an eluent to give the titlecompound (560 mg, yield 89%) as white crystals.

IR (neat) cm⁻ :2200, 1600, 1540, 1510.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.39(1H, d, J=2.44Hz), 7.55(1H, dd,J=9.16, 2.44Hz), 6.45(1H, d, J=9.16Hz), 3.55(4H, q, J=7.30Hz), 1.20(6H,t, J=7.30Hz).

Into a solution of 6-diethylamino-3-cyanopyridine (460 mg, 2.63 mmol) in1-propanol (15 ml) was passed hydrogen chloride gas at a temperature of0°-5° C. for 30 minutes. The reactor was tight sealed, and the mixturewas stirred at 0° C. over night. After the reaction was completed, thereaction mixture was concentrated under reduced pressure, and theresidue was added to a concentrated sodium carbonate solution. After itwas confirmed that the solution showed an alkaline pH (9 or more), itwas extracted with chloroform. The chloroform layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givea crude product of propyl 6-diethylamino-3-pyridinecarboximidate as anoil. The oil was dissolved in acetonitrile (2 ml), and an aqueoussolution (5 ml) of NaH₂ PO₄ ·2H₂ O (1.62 g, 10.4 mmol), Na₂ HPO₄ (370mg, 2.61 mmol) and cyanamide (220 mg, 5.24 mmol) was added to thesolution. The mixture was stirred at room temperature over night. Afterthe reaction was completed, the reaction mixture was extracted withchloroform, and the chloroform layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue obtainedwas purified by silica gel column chromatography with a mixed solvent ofmethanol and chloroform to give propylN-cyano-6-diethylamino-3-pyridinecarboximidate (630 mg, yield 92%) as acolorless oil.

IR (neat) cm⁻¹ :2960, 2180, 1580, 1280.

¹ H-NMR (500 MHZ, CDCl₃): δ (ppm) 8.90(1H, d, J=2.45Hz), 8.38(1H, d,J=2.44Hz), 7.55(1H, dd, J=9.16, 2.44Hz), 6.47(1H, d, J=9.16Hz), 4.31(2H,t, J=6.41Hz), 3.59(4H, q, J=7.33Hz), 1.81(2H, m), 1.22 (6H, t,J=7.33Hz), 1.03 (3H, t, J=7.21Hz).

To a solution of 2-nitroxyethylamine hydrochloride (314 mg, 2.20 mmol)in methanol (3 ml) was added sodium methoxide (115 mg, 2.13 mmol)followed by a solution of propylN-cyano-6-diethylamino-3-pyridinecarboximidate (370 mg, 1.42 mmol) inmethanol (2 ml), and the mixture was stirred at room temperature for 5hours. After the reaction was completed, the reaction mixture wasconcentrated to dryness under reduced pressure. The residue wassuspended in water and extracted with ethyl acetate. The ethyl acetatelayer was washed with a saturated saline solution, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue thusobtained was purified by silica gel column chromatography with a mixedsolvent of ethyl acetate and hexane as an eluent to give the titlecompound (183 mg, yield 42%) as colorless crystals.

Mp 119° C.

IR (KBr) cm⁻¹ :2160, 1635, 1565, 1275.

¹ H-NMR (500 MHz, CDCl₃): δ (ppm) 8. 41(1H, d, J=3.05Hz), 7.84(1H, dd,J=9.15, 3.05Hz), 6.52(1H, brs), 6.50(1H, d, J=9.15Hz), 4.68(2H, t,J=5.18Hz), 3.82(2H, m), 3.55(4H, q, J=7.32Hz), 1.20(6H, t, J=7.33Hz).

MS 306 (M⁺), 244 [(M-ONO₂)⁺ ].

Example 5 Preparation of5-N-Butylamino-N-Cyano-N'-(2-nitroxyethyl)-3pyridinecarboximidamide

To a solution of 2-nitroxyethylamine hydrochloride (443 mg, 3.11 mmol)in DMF (2 ml) was added sodium methoxide (153 mg, 2.83 mmol)-followed bya solution of propyl 5-n-butylamino-N-cyano-3-pyridinecarboximidate (147mg, 0.56 mmol) described in Example 12 of Experimental Example 1 in DMF(1 ml), and the mixture was stirred at room temperature for 4 hours.After the reaction was completed, the reaction mixture was concentratedto dryness under reduced pressure. The residue was suspended in waterand extracted with chloroform. The chloroform layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatographywith a mixed solvent of methanol and chloroform as an eluent to give thetitle compound (145 mg, yield 83%) as colorless crystals.

Mp 103.5° C.

IR (KBr) cm⁻¹ :3230, 2170, 1630, 1580, 1555, 1275.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 8.01(1H, d, J=2.6Hz), 7.91(1H, d,J=1.8Hz), 7.80(1H, brt), 7.15(1H, dd, J=2.6, 1.8Hz), 4.71(2H, t,J=5.1Hz), 4.49(1H, brs), 3.82(2H, m), 3.12(2H, m), 1.8-1.2(4H, m),0.96(3H, t, J=6.37).

MS 306 (M⁺), 244 [(M-ONO₂)⁺ ].

Example 6 Preparation ofN-Cyano-N'-(2-nitroxyethyl)-5-isopropylamino-3-pyridinecarboximidamide

To a solution of 2-nitroxyethylamine hydrochloride (95 mg, 0.67 mmol) inDMF (1 ml) was added sodium methoxide (25 mg, 0.46 mmol) followed by asolution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (80mg, 0.33 mmol) described in Example 11 of Experimental Example 1 in DMF(1 ml), and the mixture was stirred at room temperature for 3 hours.After the reaction was completed, the reaction mixture was concentratedto dryness under reduced pressure. The residue was suspended in waterand extracted with chloroform. The chloroform layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatographywith a mixed solvent of methanol and chloroform as an eluent to give thetitle compound (26 mg, yield 27%) as colorless crystals.

Mp 123° C.

IR (KBr) cm⁻¹ :3220, 2200, 1640, 1590, 1560, 1280, 1000, 845.

¹ H-NMR (90 MHz, CDCl₃ -CD₃ OD): δ (ppm) 7.97(1H, d, J=3.9Hz), 7.86(1H,d, J=1.5Hz), 7.03(1H, dd, J=3.9, 1.5Hz), 4.62(2H, t, J=5.0Hz), 3.80(1H,m), 3.57(1H, m), 1.25(6H, d, J=6.4Hz).

MS 292 (M⁺), 230 [(M-ONO²)⁺ ].

Example 7 Preparation of5-acetylamino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide

To a solution of5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide (105 mg,0.42 mmol) (see Example 1) in pyridine (1 ml) was added acetyl chloride(45 μl, 0.63 mmol), and the mixture was reacted at room temperature for1 hour. After the reaction was completed, a cold aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethylacetate. The ethyl acetate layer was washed with brine, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue thus obtained was purified by silica gel column chromatographywith a mixed solvent of methanol and chloroform as an eluent to give thetitle compound (116 mg, yield 95%) as hygroscopic powder.

IR (KBr) cm⁻¹ :2180, 1680, 1635, 1565, 1450, 1280.

¹ H-NMR (90 MHz, CDCl₃): δ (ppm) 10.5(1H, brs), 9.54(1H, brt), 8.90(1H,d, J=2.4Hz), 8.42(1H, d, J=2.0Hz), 8.27(1H, dd, J=2.4, 2.0Hz), 4.75(2H,t, J=5.1Hz), 3.73(2H, m), 3.31(3H, s).

MS 292 (M⁺), 230 [(M-ONO₂)⁺ ].

Example 8 (Tablet/in 1 tablet)

    ______________________________________                                        5-amino-N-cyano-N'-(2-nitroxyethyl)-3-                                                                  2 mg                                                pyridinecarboximidamide                                                       Lactose                   75.5 mg                                             Maize starch              18 mg                                               Talc                      4 mg                                                Magnesium stearate        0.5 mg                                              Total                     100 mg                                              ______________________________________                                    

The aforementioned ingredients are mixed together and pressed into atablet.

Example 9 (Capsule/in 1 capsule)

    ______________________________________                                        5-amino-N-cyano-N'-(2-nitroxyethyl)-3-                                                                  5 mg                                                pyridinecarboximidamide                                                       Lactose                   94 mg                                               Magnesium stearate        1 mg                                                Total                     100 mg                                              ______________________________________                                    

The aforementioned ingredients are mixed together and capsulated to forma capsule.

Example 10 (Injection/in 1 vial)

    ______________________________________                                        5-amino-N-cyano-N'-(2-nitroxyethyl)-3-                                                                 1      mg                                            pyridinecarboximidamide                                                       Maltose                  25     mg                                            Distilled water for injection                                                                          as required                                          Total                    2      ml                                            ______________________________________                                    

The aforementioned ingredients are mixed together, filtered and filledinto a vial. After lyophilization, the vial is tight sealed forinjection.

Industrial Applicability

The compounds according to the present invention have vasodilatingeffect, more specifically, hypotensive activity or antianginal effect,which are thus useful as antihypertensive agents or antianginal agents.

We claim:
 1. A pyridinecarboximidamide represented by the formula (I):##STR4## wherein R¹ is selected from a hydroxyalkyl, carboxyl, amino,acylamino, alkylamino, dialkylamino, aralkylamino, alkylsulfonamide,bisalkylsulfonylamino or hydroxyl group, R² represents a hydrogen atomand R³ represents a nitroxyl, 2-chlorophenyl or phenyl group, orR¹represents a hydrogen atom, R² represents a hydroxyalkyl, carboxyl,amino, acylamino, alkylamino, dialkylamino, aralkylamino,alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group and R³represents a nitroxyl, 2-chlorophenyl or phenyl group; or an acid adductsalt thereof.
 2. A pyridinecarboximidamide or an acid adduct saltthereof according to claim 1, which is a compound represented by theformula (I-a): ##STR5## wherein R¹ is selected from a hydroxyalkyl,carboxyl, amino, acylamino, alkylamino, dialkylamino, aralkylamino,alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group, R² representsa hydrogen atom and R⁴ represents a hydrogen or chlorine atom, orR¹represents a hydrogen atom, R² represents a hydroxyalkyl, carboxyl,amino, acylamino, alkylamino, dialkylamino, aralkylamino,alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group and R⁴represents a hydrogen or chlorine atom.
 3. A pyridinecarboximidamide oran acid adduct salt thereof according to claim 1, which is a compoundrepresented by the formula (I-b): ##STR6## wherein R¹ is selected from ahydroxyalkyl, carboxyl, amino, acylamino, alkylamino, dialkylamino,aralkylamino, alkylsulfonamide, bisalkylsulfonylamino or hydroxyl group,R² represents a hydrogen atom, orwhen R¹ represents a hydrogen atom, R²represents a hydroxyalkyl, carboxyl, amino, acylamino, alkylamino,dialkylamino, aralkylamino, alkylsulfonamide, bisalkylsulfonylamino orhydroxyl group.
 4. A pyridinecarboximidamide or an acid adduct saltthereof according to claim 1, wherein, as R¹ and R² in the formula (I)[are such that the alkyl group has 1 to 5 carbon atoms,] alkyl of thehydroxyalkyl group has 1 to 5 carbon atoms, acyl of the acylamino groupis acetyl, propionyl or benzoyl, alkyl of the alkylamino group has 1 to5 carbon atoms, alkyl of the dialkylamino group has 1 to 5 carbon atoms,the aralkylamino group is benzylamino, alkyl of the alkylsulfonamidegroup has 1 to 5 carbon atoms, and alkyl of the bisalkylsulfonylaminogroup has 1 to 5 carbon atoms.
 5. A pyridinecarboximidamide or an acidadduct salt adduct thereof according to claim 2, wherein R¹ and R² inthe formula (I-a) [are such that the alkyl group has 1 to 5 carbonatoms,] alkyl of the hydroxyalkyl group has 1 to 5 carbon atoms, acyl ofthe acylamino group is acetyl, propionyl or benzoyl, alkyl of thealkylamino group has 1 to 5 carbon atoms, alkyl of the dialkylaminogroup has 1 to 5 carbon atoms, the aralkylamino group is benzylamino,alkyl of the alkylsulfonamide group has 1 to 5 carbon atoms, and alkylof the bisalkylsulfonylamino group has 1 to 5 carbon atoms.
 6. Apyridinecarboximidamide or an acid adduct salt adduct thereof accordingto claim 3, wherein R¹ and R² in the formula (I-b) [are such that thealkyl group has 1 to 5 carbon atoms,] alkyl of the hydroxyalkyl grouphas 1 to 5 carbon atoms, acyl of the acylamino group is acetyl,propionyl or benzoyl, alkyl of the alkylamino group has 1 to 5 carbonatoms, alkyl of the dialkylamino group has 1 to 5 carbon atoms, thearalkylamino group is benzylamino, alkyl of the alkylsulfonamide grouphas 1 to 5 carbon atoms, and alkyl of the bisalkylsulfonylamino grouphas 1 to 5 carbon atoms.
 7. A pyridinecarboximidamide or an acid adductsalt adduct thereof according to claim 5, which is selected from thegroup consisting of the following compounds or an acid adduct saltthereof:1)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxymethyl-3-pyridinecarboximidamide,2) 5-carboxy-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide, 3)6-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide,4)5-amino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,5)5-acetamide-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,6)5-benzamide-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,7)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-dimethylamino-3-pyridinecarboximidamide,8)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-ethylamino-3-pyridinecarboximidamide,9)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-isopropylamino-3-pyridinecarboximidamide,10)5-n-butylamino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,11)5-benzylamino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,12)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-methanesulfonamide-3-pyridinecarboximidamide,13)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-bismethanesulfonylamino-3-pyridinecarboximidamide,14) 5-amino-N-cyano-N'-(2-phenethyl)-3-pyridinecarboximidamide, and 15)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxy-3-pyridinecarboximidamide.8. A pyridinecarboximidamide or an acid adduct salt thereof according toclaim 6, which is selected from the group consisting of the followingcompounds or an acid adduct salt thereof:1)5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 2)N-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 3)6-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 4)N-cyano-6-diethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 5)5-n-butylamino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 6)N-cyano-N'-(2-nitroxyethyl)-5-isopropylamino-3-pyridinecarboximidamide,and 7)5-acetylamino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide. 9.A pyridinecarboximidamide or an acid adduct salt thereof according toclaim 5, which is the following compound or an acid adduct saltthereof:5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.10. A pyridinecarboximidamide or an acid adduct salt thereof accordingto claim 6, which is the following compound or an acid adduct saltthereof:5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide.11. A pharmaceutical composition useful for treating hypertensioncomprising a pyridinecarboximidamide represented by the formula (I-a) oran acid adduct salt thereof as set forth in any one of claims 2, 5 and7, together with a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition according to claim 11, wherein thepyridinecarboximidamide or an acid adduct salt thereof is the followingcompound:5-amino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridine-carboximidamide.13. A pharmaceutical composition useful for treating hypertensioncomprising a pyridinecarboximidamide represented by the formula (I-b) oran acid adduct salt thereof as set forth in any one of claims 3, 6 and8, together with a pharmaceutically acceptable carrier.
 14. Apharmaceutical composition according to claim 13, wherein thepyridinecarboximidamide or an acid adduct salt thereof is the followingcompound:5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridine-carboximidamide.
 15. Apharmaceutical composition useful for treating angina pectoriscomprising a pyridinecarboximidamide represented by the formula (I-b) oran acid adduct salt thereof as set forth in any one of claims 3, 6 and8, together with a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition according to claim 15, wherein thepyridinecarboximidamide or an acid adduct salt thereof is the followingcompound:5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridine-carboximidamide.
 17. Amethod for the treatment of hypertension, wherein apyridinecarboximidamide represented by the formula (I-a) or an acidadduct salt thereof as set forth in any one of claims 2, 5 and 7 isadministered to a patient who needs the treatment of hypertension.
 18. Amethod for the treatment of hypertension according to claim 17, whereinthe pyridinecarboximidamide or an acid adduct salt thereof is thefollowingcompound:5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide.19. A method for the treatment of hypertension wherein apyridinecarboximidamide represented by the formula (I-b) or an acidadduct salt thereof as set forth in any one of claims 3, 6 and 8 isadministered to a patient who needs the treatment of hypertension.
 20. Amethod for the treatment of hypertension according to claim 19 , whereinthe pyridinecarboximidamide or an acid adduct salt thereof is thefollowing compound:5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide.
 21. Amethod for the treatment of angina pectoris, wherein apyridinecarboximidamide represented by the formula (I-b) or an acidadduct salt thereof as set forth in any one of claims 3, 6 and 8 isadministered to a patient of angina pectoris.
 22. A method for thetreatment of angina pectoris according to claim 21, wherein thepyridinecarboximidamide or an acid adduct salt thereof is the followingcompound:5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide.23. A pyridinecarboximidamide represented by the formula (I) ##STR7##wherein R¹ is selected from a hydroxyalkyl, amino, acylamino oralkylamino group, R² represents a hydrogen atom, and R³ represents anitroxyl, 2-chlorophenyl or phenyl group, orR¹ represents a hydrogenatom, R² represents a hydroxyalkyl, amino, acylamino or alkylaminogroup, and R³ represents a nitroxyl, 2-chlorophenyl or phenyl group; oran acid adduct salt thereof.
 24. A pyridinecarboximidamide or an acidadduct salt thereof according to claim 23, which is a compoundrepresented by the formula (I-a): ##STR8## wherein R¹ is selected from ahydroxyalkyl, amino, acylamino or alkylamino group, R² represents ahydrogen atom and R⁴ represents a hydrogen or chlorine atom, orR¹represents a hydrogen atom, R² represents hydroxyalkyl, amino, acylaminoor alkylamino group and R⁴ represents a hydrogen or chlorine atom.
 25. Apyridinecarboximidamide or an acid adduct salt thereof according toclaim 23, which is a compound represented by the formula (I -b):##STR9## wherein R¹ is selected from a hydroxyalkyl, amino, acylamino oralkylamino group, R² represents a hydrogen atom, orR¹ represents ahydrogen atom, R² represents a hydroxyalkyl, amino, acylamino oralkylamino group.
 26. A pyridinecarboximidamide or an acid adduct saltthereof according to claim 23, wherein, R¹ and R² in the formula (I),alkyl of the hydroxyalkyl group has 1 to 5 carbon atoms, acyl of theacylamino group is acetyl, propionyl or benzoyl and alkyl of thealkylamino group has 1 to 5 carbon atoms.
 27. A pyridinecarboximidamideor an acid adduct salt thereof according to claim 24, wherein, R¹ and R²in the formula (I-a), alkyl of the hydroxyalkyl group has 1 to 5 carbonatoms, acyl of the acylamino group is acetyl, propionyl or benzoyl andalkyl of the alkylamino group has 1 to 5 carbon atoms.
 28. Apyridinecarboximidamide or an acid adduct salt thereof according toclaim 25, wherein, R¹ and R² in the formula ( I -b) , alkyl of thehydroxyalkyl group has 1 to 5 carbon atoms, acyl of the acylamino groupis acetyl, propionyl or benzoyl and alkyl of-the alkylamino group has 1to 5 carbon atoms.
 29. A pyridinecarboximidamide or an acid adduct saltthereof according to claim 27, which is selected from the groupconsisting of the following compounds or an acid adduct salt thereof:1)N-cyano-N'-[2-(2-chlorophenyl)ethyl]-5-hydroxymethyl-3-pyridinecarboximidamide,2)6-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl)-3-pyridinecarboximidamide,3)5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide,4) 5-acetamide-N-cyano-N'-[2-(2-chlorophenyl)]3-pyridinecarboximidamide,5)N-cyano-N'-[2-(2-chlorophenyl)ethyl)-5-ethylamino-3-pyridinecarboximidamide,6)N-cyano-N'-[2-(2-chlorophenyl)ethyl)-5-isopropylamino-3-pyridinecarboximidamide,7)5-n-butylamino-N-cyano-N'-[2-(2chlorophenyl)ethyl]-3-pyridinecarboximidamide,and 8) 5-amino-N-cyano-N'-(2-phenethyl)-3-pyridinecarboximidamide.
 30. Apyridinecarboximidamide or an acid adduct salt thereof according toclaim 28, which is selected from the group consisting of the followingcompounds or an acid adduct salt thereof:1)5-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 2)N-cyano-5-ethylamino-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 3)6-amino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 4)5-n-butylamino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide, 5)N-cyano-N'-(2-nitroxyethyl)-5-isopropylamino-3-pyridinecarboximidamide,and 6)5-acetylamino-N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide.